HBeAg-negative Chronic Hepatitis B
Conditions
Keywords
Hepatitis, Tenofovir, Viread
Brief summary
The primary objective of this study is to compare the efficacy, safety, and tolerability of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) in treatment-naive and treatment-experienced adults with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection.
Detailed description
Study GS-US-320-0108 is a multi-center clinical trial, planned to enroll participants in multiple countries, including China. However, due to the review timeline difference in China, full enrollment was reached in the main study before China was able to participate. Therefore, details for the China cohort was registered separately (NCT02836236) on ClinicalTrials.gov as the China cohort will not be part of the main study analysis.
Interventions
DRUGTAF
25 mg tablet administered orally once daily
DRUGTDF
300 mg tablet administered orally once daily
DRUGTAF Placebo
Tablet administered orally once daily
DRUGTDF Placebo
Tablet administered orally once daily
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures. * Adult males and non-pregnant, non-lactating females. * Documented evidence of chronic HBV infection. * Hepatitis e antigen (HBeAg)-negative, chronic hepatitis B with all of the following: * HBeAg-negative and hepatitis B e antibody (HBeAb) positive at screening. * Screening HBV DNA ≥ 2 x 10\^4 IU/mL. * Screening serum alanine aminotransferase (ALT) level \> 60 U/L (males) or \> 38 U/L (females) and ≤ 10 x the upper limit of the normal range (ULN). * Treatment-naive participants (defined as \< 12 weeks of oral antiviral treatment with any nucleoside or nucleotide analogue), OR treatment-experienced participants (defined as participants meeting all entry criteria \[including HBV DNA and serum ALT criteria\] and with ≥ 12 weeks of previous treatment with any nucleoside or nucleotide analogue). * Previous treatment with interferon (pegylated or non pegylated) must have ended at least 6 months prior to Baseline. * Adequate renal function. * Normal electrocardiogram (ECG). Key
Exclusion criteria
* Females 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, human immunodeficiency virus (HIV), or hepatitis D virus. * Evidence of hepatocellular carcinoma. * Any history of, or current evidence of, clinical hepatic decompensation. * Abnormal hematological and biochemical parameters, including aspartate aminotransferase (AST) \> 10 x ULN * Received solid organ or bone marrow transplant. * History of malignancy within the past 5 years, with the exception of specific cancers that are cured by surgical resection; individuals under evaluation for possible malignancy are not eligible. * Currently receiving therapy with immunomodulators (eg, corticosteroids), investigational agents, nephrotoxic agents, or agents capable of modifying renal excretion. * Individuals receiving ongoing therapy with drugs not to be used with tenofovir alafenamide or tenofovir disoproxil fumarate 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 participant compliance. * Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for the study or unable to comply with dosing requirements. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL | Week 48 | The primary efficacy endpoint was determined by the achievement of HBV DNA \< 29 IU/mL at Week 48. |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Spine BMD at Week 48 | Baseline, Week 48 |
| Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | Baseline, Week 48 |
| Change From Baseline in Serum Creatinine at Week 48 | Baseline, Week 48 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Up to 48 weeks | Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method. |
Countries
Australia, Canada, France, Hong Kong, India, Italy, Japan, New Zealand, Poland, Romania, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in East Asia, Europe, North America, Australia, India, and New Zealand.
Pre-assignment details
877 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| TAF 25 mg Double-blind Phase: Tenofovir alafenamide (Vemlidy®; TAF) 25 mg + tenofovir disoproxil fumarate (TDF) placebo tablets administered once daily for up to 96 weeks (per amendment 1 & 2) or 144 weeks (per amendment 3).
Open-label TAF extension Phase: After Week 96 or 144 in the Blinded Treatment Phase, participants were given the option to continue with OL TAF 25 mg for additional 288 or 240 weeks (Up to Week 384), respectively.
After the completion of OL TAF Extension Phase treatment or when there was early discontinuation of treatment, participants either switched to commercially available anti-HBV treatments in their country or entered follow-up phase and were followed-up every 4 weeks for 24 weeks off treatment (TFFU) for the assessment of safety. | 285 |
| TDF 300 mg Double-blind Phase: TDF 300 mg + TAF placebo tablets administered once daily for up to 96 weeks (per amendment 1 & 2) or 144 weeks (per amendment 3).
Open-label TAF extension Phase: After Week 96 or 144 in the Blinded Treatment Phase, participants were given the option to continue with OL TAF 25 mg for additional 288 or 240 weeks (Up to Week 384), respectively.
After the completion of OL TAF Extension Phase treatment or when there was early discontinuation of treatment, participants either switched to commercially available anti-HBV treatments in their country or entered follow-up phase and were followed-up every 4 weeks for 24 weeks off treatment (TFFU) for the assessment of safety. | 140 |
| Total | 425 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1: Double-blind Phase | Adverse Event | 4 | 2 | 0 | 0 |
| Period 1: Double-blind Phase | Death | 0 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Investigator's Discretion | 3 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Lost to Follow-up | 8 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Non-compliance with Study Drug | 1 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Pregnancy | 0 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Protocol Specified Criteria for Withdrawal | 1 | 0 | 0 | 0 |
| Period 1: Double-blind Phase | Randomized but Never Treated | 0 | 1 | 0 | 0 |
| Period 1: Double-blind Phase | Withdrew Consent | 7 | 4 | 0 | 0 |
| Period 2: Open-Label TAF Extension Phase | Adverse Event | 0 | 0 | 2 | 0 |
| Period 2: Open-Label TAF Extension Phase | Death | 0 | 0 | 1 | 0 |
| Period 2: Open-Label TAF Extension Phase | HbsAg Seroconversion | 0 | 0 | 1 | 0 |
| Period 2: Open-Label TAF Extension Phase | Investigator's Discretion | 0 | 0 | 3 | 4 |
| Period 2: Open-Label TAF Extension Phase | Lost to Follow-up | 0 | 0 | 6 | 0 |
| Period 2: Open-Label TAF Extension Phase | Non-compliance with Study Drug | 0 | 0 | 0 | 1 |
| Period 2: Open-Label TAF Extension Phase | Pregnancy | 0 | 0 | 0 | 1 |
| Period 2: Open-Label TAF Extension Phase | Progressive Disease | 0 | 0 | 1 | 0 |
| Period 2: Open-Label TAF Extension Phase | Protocol Specified Criteria for Withdrawal | 0 | 0 | 3 | 1 |
| Period 2: Open-Label TAF Extension Phase | Withdrew Consent | 0 | 0 | 17 | 4 |
Baseline characteristics
| Characteristic | TAF 25 mg | TDF 300 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 4 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 276 Participants | 136 Participants | 412 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 11.6 | 48 years STANDARD_DEVIATION 10.4 | 46 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 279 Participants | 140 Participants | 419 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| HBV DNA | 5.7 Log10 IU/mL STANDARD_DEVIATION 1.34 | 5.8 Log10 IU/mL STANDARD_DEVIATION 1.32 | 5.8 Log10 IU/mL STANDARD_DEVIATION 1.33 |
| IL28b Status CC | 209 Participants | 106 Participants | 315 Participants |
| IL28b Status CT | 65 Participants | 23 Participants | 88 Participants |
| IL28b Status Missing | 1 Participants | 2 Participants | 3 Participants |
| IL28b Status TT | 10 Participants | 9 Participants | 19 Participants |
| Oral antiviral (OAV) treatment status Treatment Experienced | 60 Participants | 31 Participants | 91 Participants |
| Oral antiviral (OAV) treatment status Treatment Naive | 225 Participants | 109 Participants | 334 Participants |
| Plasma HBV DNA Level < 7 log10 IU/mL | 230 Participants | 116 Participants | 346 Participants |
| Plasma HBV DNA Level ≥ 7 log10 IU/mL - < 8 log10 IU/mL | 42 Participants | 20 Participants | 62 Participants |
| Plasma HBV DNA Level ≥ 8 log10 IU/mL | 13 Participants | 4 Participants | 17 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 0 | 270 Participants | 135 Participants | 405 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 1 | 13 Participants | 5 Participants | 18 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 2 | 2 Participants | 0 Participants | 2 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 3 | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 205 Participants | 101 Participants | 306 Participants |
| Race/Ethnicity, Customized Race Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other or More Than One Race | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 71 Participants | 35 Participants | 106 Participants |
| Region of Enrollment Australia | 9 Participants | 1 Participants | 10 Participants |
| Region of Enrollment Canada | 29 Participants | 17 Participants | 46 Participants |
| Region of Enrollment France | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Hong Kong | 41 Participants | 28 Participants | 69 Participants |
| Region of Enrollment India | 26 Participants | 7 Participants | 33 Participants |
| Region of Enrollment Italy | 6 Participants | 3 Participants | 9 Participants |
| Region of Enrollment Japan | 21 Participants | 6 Participants | 27 Participants |
| Region of Enrollment New Zealand | 10 Participants | 2 Participants | 12 Participants |
| Region of Enrollment Poland | 12 Participants | 6 Participants | 18 Participants |
| Region of Enrollment Romania | 13 Participants | 8 Participants | 21 Participants |
| Region of Enrollment Russia | 22 Participants | 13 Participants | 35 Participants |
| Region of Enrollment South Korea | 30 Participants | 15 Participants | 45 Participants |
| Region of Enrollment Spain | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Taiwan | 22 Participants | 15 Participants | 37 Participants |
| Region of Enrollment Turkey | 10 Participants | 4 Participants | 14 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 1 Participants | 6 Participants |
| Region of Enrollment United States | 24 Participants | 13 Participants | 37 Participants |
| Sex: Female, Male Female | 112 Participants | 54 Participants | 166 Participants |
| Sex: Female, Male Male | 173 Participants | 86 Participants | 259 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 285 | 2 / 141 | 1 / 261 | 0 / 129 |
| other Total, other adverse events | 178 / 285 | 89 / 140 | 112 / 261 | 55 / 129 |
| serious Total, serious adverse events | 26 / 285 | 17 / 140 | 38 / 261 | 17 / 129 |
Outcome results
Primary
Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL
The primary efficacy endpoint was determined by the achievement of HBV DNA \< 29 IU/mL at Week 48.
Time frame: Week 48
Population: Full Analysis set: participants who were randomized into the study and received at least 1 dose of study drugs. Participants were analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAF 25 mg | Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL | 94.0 Percentage of participants |
| TDF 300 mg | Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL | 92.9 Percentage of participants |
Comparison: The null hypothesis was that the TAF group is at least 10% worse than the TDF group with respect to the proportion of participants with HBV DNA \< 29 IU/mL at Week 48. The alternative hypothesis was that the TAF group is less than 10% worse than the TDF group with respect to the proportion of participants with HBV DNA \< 29 IU/mL at Week 48. Noninferiority was assessed using a 95% confidence interval (CI) approach, with a noninferiority margin of 10%.95% CI: [-3.6, 7.2]
Secondary
Change From Baseline in Serum Creatinine at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data was excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Change From Baseline in Serum Creatinine at Week 48 | 0.01 mg/dL | Standard Deviation 0.091 |
| TDF 300 mg | Change From Baseline in Serum Creatinine at Week 48 | 0.02 mg/dL | Standard Deviation 0.103 |
Secondary
Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Hip Dual-Energy X-ray Absorptiometry (DXA) Analysis Set (participants who were randomized, received at least 1 dose of study drugs, and had nonmissing baseline hip BMD values) with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | -0.288 percentage change | Standard Deviation 2.1448 |
| TDF 300 mg | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | -2.156 percentage change | Standard Deviation 2.1672 |
Secondary
Percent Change From Baseline in Spine BMD at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Spine DXA Analysis Set (participants who were randomized, received at least 1 dose of study drugs, and had nonmissing baseline spine BMD values) with available data were analyzed. Participants were analyzed according to the treatment they actually received. Missing data was excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Spine BMD at Week 48 | -0.876 percentage change | Standard Deviation 2.8558 |
| TDF 300 mg | Percent Change From Baseline in Spine BMD at Week 48 | -2.514 percentage change | Standard Deviation 3.3558 |
Other Pre-specified
Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48
Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method.
Time frame: Up to 48 weeks
Population: Participants in the Safety Analysis Set with at least 1 postbaseline urine protein value were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 1 | 18.1 percentage of participants |
| TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 2 | 1.1 percentage of participants |
| TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 3 | 0 percentage of participants |
| TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 1 | 16.4 percentage of participants |
| TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 2 | 2.1 percentage of participants |
| TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 3 | 0 percentage of participants |