HBV, Chronic HBV Infection
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)-positive chronic hepatitis B virus (HBV) infection in China.
Detailed description
This study GS-US-320-0110 is an international study planned to enroll participants in global countries, including China. However, due to the review timeline difference in China, full enrollment was reached in the main study (NCT01940471) before China was able to participate. Therefore, this registration only includes the China cohorts as they were not part of the main study analysis. Data for China cohorts were analyzed separately after the main study analysis was completed.
Interventions
DRUGTAF
TAF 25 mg tablet administered orally once daily
DRUGTDF
TDF 300 mg tablet administered orally once daily
DRUGTAF Placebo
TAF placebo tablet administered orally once daily
DRUGTDF Placebo
TDF 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 * HBeAg-positive, chronic hepatitis B with all of the following: * HBeAg-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 the baseline visit * Adequate renal function * Normal 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, 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 |
|---|---|
| Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 | Week 48 |
Secondary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48 | Week 48 |
| Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | Baseline; Week 48 |
| Percent Change From Baseline in Spine BMD at Week 48 | Baseline; Week 48 |
| Change From Baseline at Week 48 in Serum Creatinine | 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
China
Participant flow
Recruitment details
Participants were enrolled at study sites in China.
Pre-assignment details
226 participants were screened in China.
Participants by arm
| Arm | Count |
|---|---|
| Double-Blind: TAF 25 mg Tenofovir alafenamide (Vemlidy®; TAF) 25 mg tablet + tenofovir disoproxil fumarate (Viread®; TDF) placebo tablet once daily for up to 144 weeks (per amendment 3.1). | 123 |
| Double-Blind: TDF 300 mg TDF 300 mg tablet + TAF placebo tablet once daily for up to 144 weeks (per amendment 3.1). | 57 |
| Total | 180 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Phase | Investigator's discretion | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Phase | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Phase | Non-compliance with study drug | 1 | 0 | 0 | 0 |
| Double-Blind Treatment Phase | Pregnancy | 3 | 1 | 0 | 0 |
| Double-Blind Treatment Phase | Randomized but Never Treated | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Phase | Withdrew Consent | 5 | 2 | 0 | 0 |
| Open-Label TAF Treatment Phase | Death | 0 | 0 | 1 | 0 |
| Open-Label TAF Treatment Phase | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Open-Label TAF Treatment Phase | Lost to Follow-up | 0 | 0 | 6 | 1 |
| Open-Label TAF Treatment Phase | Pregnancy | 0 | 0 | 1 | 0 |
| Open-Label TAF Treatment Phase | Withdrew consent | 0 | 0 | 4 | 3 |
Baseline characteristics
| Characteristic | Double-Blind: TAF 25 mg | Double-Blind: TDF 300 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 121 Participants | 57 Participants | 178 Participants |
| Age, Continuous | 34 years STANDARD_DEVIATION 9.4 | 36 years STANDARD_DEVIATION 9.5 | 34 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 123 Participants | 57 Participants | 180 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HBV DNA | 7.2 log10 IU/mL STANDARD_DEVIATION 1.65 | 7.2 log10 IU/mL STANDARD_DEVIATION 1.48 | 7.2 log10 IU/mL STANDARD_DEVIATION 1.59 |
| IL28b Status CC | 109 Participants | 52 Participants | 161 Participants |
| IL28b Status CT | 12 Participants | 5 Participants | 17 Participants |
| IL28b Status TT | 2 Participants | 0 Participants | 2 Participants |
| Oral antiviral (OAV) Treatment Status Treatment Experienced | 45 Participants | 18 Participants | 63 Participants |
| Oral antiviral (OAV) Treatment Status Treatment Naive | 78 Participants | 39 Participants | 117 Participants |
| Plasma HBV DNA Level < 8 log10 IU/mL | 74 Participants | 36 Participants | 110 Participants |
| Plasma HBV DNA Level ≥ 8 log10 IU/mL | 49 Participants | 21 Participants | 70 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 0 | 117 Participants | 54 Participants | 171 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 1 | 6 Participants | 2 Participants | 8 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 2 | 0 Participants | 1 Participants | 1 Participants |
| Proteinuria by Urinalysis (dipstick) Grade 3 | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 123 Participants | 57 Participants | 180 Participants |
| Sex: Female, Male Female | 35 Participants | 13 Participants | 48 Participants |
| Sex: Female, Male Male | 88 Participants | 44 Participants | 132 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 / 123 | 0 / 57 | 1 / 113 | 0 / 52 |
| other Total, other adverse events | 85 / 123 | 43 / 57 | 84 / 113 | 42 / 52 |
| serious Total, serious adverse events | 8 / 123 | 3 / 57 | 7 / 113 | 4 / 52 |
Outcome results
Primary
Percentage of Participants With Hepatitis B Virus (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) |
|---|---|---|
| Double-Blind: TAF 25 mg | Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 | 61.0 percentage of participants |
| Double-Blind: TDF 300 mg | Percentage of Participants With Hepatitis B Virus (HBV) DNA < 29 IU/mL at Week 48 | 68.4 percentage of participants |
Secondary
Change From Baseline at Week 48 in Serum Creatinine
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 were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: TAF 25 mg | Change From Baseline at Week 48 in Serum Creatinine | -0.003 mg/dL | Standard Deviation 0.0701 |
| Double-Blind: TDF 300 mg | Change From Baseline at Week 48 in Serum Creatinine | 0.016 mg/dL | Standard Deviation 0.092 |
Secondary
Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48
Time frame: Week 48
Population: Serologically Evaluable Full Analysis Set: participants who were randomized, had received at least 1 dose of study drug, and were HBeAg positive and anti-HBe negative or had a value missing value at baseline. Participants were analyzed according to their randomized treatment group. All missing data were treated as no HBeAg seroconversion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Double-Blind: TAF 25 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48 | 11.0 percentage of participants |
| Double-Blind: TDF 300 mg | Percentage of Participants With Hepatitis B e Antigen (HBeAg) Seroconversion to Antibody Against Hepatitis B e Antigen (Anti-HBe) at Week 48 | 8.8 percentage of participants |
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 |
|---|---|---|---|
| Double-Blind: TAF 25 mg | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | 0.624 percent change | Standard Deviation 2.2731 |
| Double-Blind: TDF 300 mg | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48 | -1.507 percent change | Standard Deviation 2.4193 |
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. Dual-energy x ray absorptiometry scans were performed only at sites in China with capability. Participants were analyzed according to the treatment they actually received. Missing data were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Double-Blind: TAF 25 mg | Percent Change From Baseline in Spine BMD at Week 48 | 0.683 percent change | Standard Deviation 3.3281 |
| Double-Blind: TDF 300 mg | Percent Change From Baseline in Spine BMD at Week 48 | -2.169 percent change | Standard Deviation 3.4503 |
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) |
|---|---|---|---|
| Double-Blind: TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 1 | 24.4 percentage of participants |
| Double-Blind: TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 2 | 0.8 percentage of participants |
| Double-Blind: TAF 25 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 3 | 0 percentage of participants |
| Double-Blind: TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 1 | 22.8 percentage of participants |
| Double-Blind: TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 2 | 3.5 percentage of participants |
| Double-Blind: TDF 300 mg | Percentage of Participants With Treatment-emergent Proteinuria by Urinalysis (Dipstick) Through Week 48 | Grade 3 | 0 percentage of participants |