Study to Evaluate Efficacy and Safety of Switching From TDF to TAF in Adults With Chronic Hepatitis B Who Are Virologically Suppressed
- Registration Number
- NCT02979613
- Lead Sponsor
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 490
- 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
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Pregnant women or women who are breastfeeding
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Males and females of reproductive potential who are unwilling to use an "effective", protocol-specified method(s) of contraception during the study.
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Co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV), or human immunodeficiency virus (HIV)
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Evidence of hepatocellular carcinoma
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Current evidence of, or recent (≤ 5 year) history of clinical hepatic decompensation
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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
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Received solid organ or bone marrow transplant
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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.
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Currently receiving therapy with immunomodulators (eg, corticosteroids), nephrotoxic agents, or agents capable of modifying renal excretion
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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
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Current alcohol or substance abuse judged by the investigator to potentially interfere with compliance
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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.
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Use of investigational agents within 3 months of screening, unless allowed by the sponsor
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TAF 25 mg TAF 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. TAF 25 mg TDF Placebo 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. TDF 300 mg TAF DB phase: TDF 300 mg + TAF placebo for up to 50 weeks. OLE phase: TAF 25 mg for up to 52 weeks. TDF 300 mg TDF DB phase: TDF 300 mg + TAF placebo for up to 50 weeks. OLE phase: TAF 25 mg for up to 52 weeks. TDF 300 mg TAF Placebo DB phase: TDF 300 mg + TAF placebo for up to 50 weeks. OLE phase: TAF 25 mg for up to 52 weeks.
- Primary Outcome Measures
Name Time Method 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 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
Name Time Method Percentage of Participants With HBV DNA Levels < 20 IU/mL (Target Detected/Not Detected) at Week 48 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 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 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 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 HBV DNA Levels ≥ 20 IU/mL at Week 96, as Determined by the Modified US FDA-Defined Snapshot Algorithm 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/mLPercentage of Participants With HBV DNA Levels < 20 IU/mL at Week 48 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 HBeAg Seroconversion at Week 48 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 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 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 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 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 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 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) 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) 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) 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) 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 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 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 Baseline; Week 48 Percent Change = Change from baseline at a postbaseline visit/baseline \* 100%.
Percent Change From Baseline in Hip BMD at Week 96 Baseline; Week 96 Percent Change = Change from baseline at a postbaseline visit/baseline \* 100%.
Percent Change From Baseline in Spine BMD at Week 48 Baseline; Week 48 Percent Change = Change from baseline at a postbaseline visit/baseline \* 100%.
Percent Change From Baseline in Spine BMD at Week 96 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 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 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.