Chronic Hepatitis B
Conditions
Brief summary
The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of GS-4774 in adults with CHB and who are currently not on treatment. Participants will be randomized to receive TDF alone or GS-4774 plus TDF for 20 weeks. After Week 20, GS-4774 will be discontinued. All participants will continue on TDF and will be followed for an additional 28 weeks. Following completion of the 48 week study period, all participants will be eligible for a treatment extension for 96 weeks.
Interventions
DRUGTenofovir disoproxil fumarate
TDF 300 mg tablet administered orally once daily
BIOLOGICALGS-4774
GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study * Documented evidence of chronic hepatitis B virus (HBV) infection, for example, hepatitis B surface antigen (HBsAg) positive for more than 6 months * Screening HBV DNA ≥ 2000 IU/mL * A negative serum pregnancy test is required for females (unless surgically sterile or \> 2 years post-menopausal) Key
Exclusion criteria
* Cirrhosis * Inadequate liver function * Co-infection with hepatitis C virus (HCV), HIV or hepatitis D virus (HDV) * Received antiviral treatment for HBV within 3 months of screening * Evidence of hepatocellular carcinoma (eg, as evidenced by recent imaging) * Significant cardiovascular, pulmonary, or neurological disease * Women who are pregnant or may wish to become pregnant during the course of the study * Received solid organ or bone marrow transplant * Received prolonged therapy with immunomodulators (eg, corticosteroids) or biologics (eg, monoclonal antibody, interferon) within 3 months of screening * Use of investigational agents within 3 months of screening * Current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance * Receipt of immunoglobulin or other blood products within 3 months prior to enrollment * History of demyelinating disease (Guillain-Barre), Bell's Palsy, Crohn's disease, Ulcerative colitis, or autoimmune disease * Documented history of yeast allergy * Known hypersensitivity to study drugs, metabolites or formulation excipients * Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc). Individuals under evaluation for possible malignancy are not eligible Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Serum HBsAg From Baseline to Week 24 | Baseline to Week 24 | The change from baseline to Week 24 in HBsAg was analyzed using a mixed effect model for repeated measures (MMRM). The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% confidence intervals (CIs). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in HBsAg From Baseline to Week 48 | Baseline to Week 48 | The change from baseline to Week 48 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs. |
| Percentage of Participants With HBsAg Loss at Week 24 | Baseline to Week 24 | HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. |
| Percentage of Participants With HBsAg Loss at Week 48 | Baseline to Week 48 | HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. |
| Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24 | Baseline to Week 24 | HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window. |
| Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48 | Baseline to Week 48 | HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window. |
| Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | Baseline to Week 12 | HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. |
| Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | Baseline to Week 24 | HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. |
| Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | Baseline to Week 48 | HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window. |
| Mean Change in HBsAg From Baseline to Week 12 | Baseline to Week 12 | The change from baseline to Week 12 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs. |
| Percentage of Participants With HBeAg Loss at Week 48 | Baseline to Week 48 | HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. |
| Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24 | Baseline to Week 24 | HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window. |
| Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48 | Baseline to Week 48 | HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window. |
| Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | Week 24 | The LLOQ was defined as 20 IU/mL. |
| Percentage of Participants With HBV DNA < LLOQ at Week 48 | Week 48 | The LLOQ was defined as 20 IU/mL. |
| Percentage of Participants Experiencing Virologic Breakthrough at Week 24 | Baseline to Week 24 | Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been \< 69 IU/mL, or having had ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough. |
| Percentage of Participants Experiencing Virologic Breakthrough at Week 48 | Baseline to Week 48 | Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been \< 69 IU/mL, or a ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough. |
| Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available | Baseline to Week 48 | Resistance surveillance analysis was conducted at Week 48 or Early Discontinuation (with at least 24 weeks of exposure to TDF) for any participants who met inclusion criteria (HBV DNA ≥ 69 IU/mL). Drug-resistant mutation status was assessed using HBV polymerase/ reverse transcriptase (pol/RT) population sequencing. |
| Percentage of Participants With HBeAg Loss at Week 24 | Baseline to Week 24 | HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. |
Countries
Canada, Italy, New Zealand, Romania, South Korea, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Europe, New Zealand, and South Korea. The first participant was screened on 24 July 2014. The last study visit occurred on 30 May 2018.
Pre-assignment details
254 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| TDF 48 Weeks Participants received TDF 300 mg tablet orally once daily for 48 weeks during the main study. Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP). | 27 |
| TDF + GS-4774 2 YU Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 2 yeast units (YU) administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP). | 57 |
| TDF + GS-4774 10 YU Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 10 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP). | 56 |
| TDF + GS-4774 40 YU Participants received TDF 300 mg tablet orally once daily for 48 weeks + GS-4774 40 YU administered via subcutaneous injection every 4 weeks for 20 weeks (total of 6 doses). Participants had the option to continue receiving TDF 300 mg tablet orally once daily for up to 144 weeks (in OTEP). | 55 |
| Total | 195 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| OTEP (Weeks 48 to 144) | Lost to Follow-up | 0 | 0 | 1 | 0 |
| OTEP (Weeks 48 to 144) | Pregnancy | 0 | 0 | 1 | 0 |
| OTEP (Weeks 48 to 144) | Withdrew Consent | 1 | 0 | 1 | 2 |
| Study Treatment Phase (Weeks 1 to 48) | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Study Treatment Phase (Weeks 1 to 48) | Pregnancy | 0 | 0 | 1 | 0 |
| Study Treatment Phase (Weeks 1 to 48) | Withdrawal by Subject | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | TDF + GS-4774 40 YU | TDF + GS-4774 10 YU | TDF 48 Weeks | TDF + GS-4774 2 YU |
|---|---|---|---|---|---|
| Age, Continuous | 44 years STANDARD_DEVIATION 10.6 | 43 years STANDARD_DEVIATION 11.6 | 44 years STANDARD_DEVIATION 9.1 | 44 years STANDARD_DEVIATION 10.3 | 46 years STANDARD_DEVIATION 11.2 |
| Baseline Alanine Aminotransferase (ALT) Category ≤ ULN | 54 Participants | 12 Participants | 21 Participants | 6 Participants | 15 Participants |
| Baseline Alanine Aminotransferase (ALT) Category > ULN | 141 Participants | 43 Participants | 35 Participants | 21 Participants | 42 Participants |
| Baseline Hepatitis B Surface Antigen (HBsAg) | 3.7 log10 IU/mL STANDARD_DEVIATION 0.84 | 3.7 log10 IU/mL STANDARD_DEVIATION 0.8 | 3.7 log10 IU/mL STANDARD_DEVIATION 0.94 | 3.8 log10 IU/mL STANDARD_DEVIATION 0.78 | 3.7 log10 IU/mL STANDARD_DEVIATION 0.82 |
| Baseline Hepatitis B Virus (HBV) DNA | 5.9 log10 IU/mL STANDARD_DEVIATION 1.88 | 6.0 log10 IU/mL STANDARD_DEVIATION 1.8 | 5.8 log10 IU/mL STANDARD_DEVIATION 1.97 | 6.0 log10 IU/mL STANDARD_DEVIATION 1.64 | 5.8 log10 IU/mL STANDARD_DEVIATION 1.99 |
| Hepatitis B Envelope Antigen (HBeAg) Status at Baseline Negative | 119 Participants | 34 Participants | 33 Participants | 17 Participants | 35 Participants |
| Hepatitis B Envelope Antigen (HBeAg) Status at Baseline Positive | 76 Participants | 21 Participants | 23 Participants | 10 Participants | 22 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 192 Participants | 55 Participants | 56 Participants | 27 Participants | 54 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Asian | 155 Participants | 45 Participants | 44 Participants | 24 Participants | 42 Participants |
| Race/Ethnicity, Customized Race Black or African American | 9 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 3 Participants | 1 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 28 Participants | 6 Participants | 8 Participants | 1 Participants | 13 Participants |
| Region of Enrollment Canada | 46 Participants | 17 Participants | 9 Participants | 6 Participants | 14 Participants |
| Region of Enrollment Italy | 13 Participants | 2 Participants | 5 Participants | 1 Participants | 5 Participants |
| Region of Enrollment New Zealand | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Romania | 7 Participants | 3 Participants | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment South Korea | 56 Participants | 12 Participants | 19 Participants | 9 Participants | 16 Participants |
| Region of Enrollment United States | 72 Participants | 21 Participants | 20 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Female | 77 Participants | 22 Participants | 23 Participants | 9 Participants | 23 Participants |
| Sex: Female, Male Male | 118 Participants | 33 Participants | 33 Participants | 18 Participants | 34 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 / 27 | 0 / 57 | 0 / 56 | 0 / 55 |
| other Total, other adverse events | 12 / 27 | 41 / 57 | 50 / 56 | 53 / 55 |
| serious Total, serious adverse events | 2 / 27 | 1 / 57 | 1 / 56 | 1 / 55 |
Outcome results
Primary
Mean Change in Serum HBsAg From Baseline to Week 24
The change from baseline to Week 24 in HBsAg was analyzed using a mixed effect model for repeated measures (MMRM). The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% confidence intervals (CIs).
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set (all participants who were randomized and received at least 1 dose of study drug) with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TDF 48 Weeks | Mean Change in Serum HBsAg From Baseline to Week 24 | -0.079 log10 IU/mL |
| TDF + GS-4774 2 YU | Mean Change in Serum HBsAg From Baseline to Week 24 | -0.096 log10 IU/mL |
| TDF + GS-4774 10 YU | Mean Change in Serum HBsAg From Baseline to Week 24 | -0.016 log10 IU/mL |
| TDF + GS-4774 40 YU | Mean Change in Serum HBsAg From Baseline to Week 24 | -0.135 log10 IU/mL |
Comparison: The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.p-value: 0.80595% CI: [-0.155, 0.12]Mixed-Effect Model for Repeated Measures
Comparison: The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.p-value: 0.3795% CI: [-0.075, 0.202]Mixed-Effect Model for Repeated Measures
Comparison: The null hypotheses was that the mean change from baseline in serum HBsAg in each of the TDF + GS-4774 groups was equal to the mean change from baseline in serum HBsAg in the TDF only group. Each null hypothesis was tested against the 2-sided alternative hypothesis that the mean change from baseline in serum HBsAg was not equal between each of the respective GS-4774 dose groups and the TDF only group.p-value: 0.42695% CI: [-0.194, 0.082]Mixed-Effect Model for Repeated Measures
Secondary
Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24
HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24 | 4.3 percentage of participants |
| TDF + GS-4774 40 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 24 | 0.0 percentage of participants |
Secondary
Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48
HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBeAg loss and seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBeAg loss within the targeted time window.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48 | 4.3 percentage of participants |
| TDF + GS-4774 40 YU | Composite Endpoint Measuring the Percentage of Participants With HBeAg Loss and HBeAg Seroconversion at Week 48 | 9.5 percentage of participants |
Secondary
Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24
HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 24 | 0.0 percentage of participants |
Secondary
Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48
HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window. HBsAg loss and seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit and the participant must have achieved HBsAg loss within the targeted time window.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Composite Endpoint Measuring the Percentage of Participants With HBsAg Loss and HBsAg Seroconversion at Week 48 | 0.0 percentage of participants |
Secondary
Mean Change in HBsAg From Baseline to Week 12
The change from baseline to Week 12 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs.
Time frame: Baseline to Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TDF 48 Weeks | Mean Change in HBsAg From Baseline to Week 12 | -0.060 log10 IU/mL |
| TDF + GS-4774 2 YU | Mean Change in HBsAg From Baseline to Week 12 | -0.061 log10 IU/mL |
| TDF + GS-4774 10 YU | Mean Change in HBsAg From Baseline to Week 12 | -0.012 log10 IU/mL |
| TDF + GS-4774 40 YU | Mean Change in HBsAg From Baseline to Week 12 | -0.095 log10 IU/mL |
Secondary
Mean Change in HBsAg From Baseline to Week 48
The change from baseline to Week 48 in HBsAg was analyzed using a MMRM. The model included treatment groups, ALT levels (\> ULN or ≤ ULN) at baseline, HBeAg status (positive or negative) at baseline, HBsAg level at baseline, visit and treatment-by-visit interaction as fixed effects and visit as a repeated measurement. Estimated least square means of treatment effects are presented with the 95% CIs.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TDF 48 Weeks | Mean Change in HBsAg From Baseline to Week 48 | -0.145 log10 IU/mL |
| TDF + GS-4774 2 YU | Mean Change in HBsAg From Baseline to Week 48 | -0.136 log10 IU/mL |
| TDF + GS-4774 10 YU | Mean Change in HBsAg From Baseline to Week 48 | -0.086 log10 IU/mL |
| TDF + GS-4774 40 YU | Mean Change in HBsAg From Baseline to Week 48 | -0.165 log10 IU/mL |
Secondary
Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available
Resistance surveillance analysis was conducted at Week 48 or Early Discontinuation (with at least 24 weeks of exposure to TDF) for any participants who met inclusion criteria (HBV DNA ≥ 69 IU/mL). Drug-resistant mutation status was assessed using HBV polymerase/ reverse transcriptase (pol/RT) population sequencing.
Time frame: Baseline to Week 48
Population: Participants with at least 24 weeks of exposure to TDF and with HBV DNA ≥ 69 IU/mL at Week 48 or Early Discontinuation were analyzed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TDF 48 Weeks | Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available | 0 Participants |
| TDF + GS-4774 2 YU | Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available | 0 Participants |
| TDF + GS-4774 10 YU | Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available | 0 Participants |
| TDF + GS-4774 40 YU | Number of Participants With Drug-Resistance Mutations at Week 48 or at the Last Visit Available | 0 Participants |
Secondary
Percentage of Participants Experiencing Virologic Breakthrough at Week 24
Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been \< 69 IU/mL, or having had ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants Experiencing Virologic Breakthrough at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 24 | 1.8 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 24 | 1.8 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 24 | 0.0 percentage of participants |
Secondary
Percentage of Participants Experiencing Virologic Breakthrough at Week 48
Virologic breakthrough was defined as HBV DNA ≥ 69 IU/mL after having been \< 69 IU/mL, or a ≥ 1.0 log10 increase in HBV DNA from nadir. Two consecutive visits that met the definition were required for a participant to be classified as having had virologic breakthrough.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants Experiencing Virologic Breakthrough at Week 48 | 3.7 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 48 | 5.3 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 48 | 5.4 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants Experiencing Virologic Breakthrough at Week 48 | 0.0 percentage of participants |
Secondary
Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12
HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 12
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 3.7 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 3.5 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 3.5 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 5.5 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 12 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
Secondary
Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24
HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 5.3 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 7.3 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 24 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
Secondary
Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48
HBsAg with a ≥ 0.5 or ≥ 1.0 log10 IU/mL decline was defined as ≥ 0.5 or ≥ 1.0 decline from baseline in log10 IU/mL serum HBsAg at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 11.1 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF 48 Weeks | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 5.3 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 7.1 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 2.0 log10 IU/mL Decline | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 0.5 and < 1.0 log10 IU/mL Decline | 7.3 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With a ≥ 0.5 Log10 IU/mL or a ≥ 1.0 Log10 IU/mL Decline in HBsAg at Week 48 | ≥ 1.0 and < 2.0 log10 IU/mL Decline | 1.8 percentage of participants |
Secondary
Percentage of Participants With HBeAg Loss at Week 24
HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBeAg Loss at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBeAg Loss at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBeAg Loss at Week 24 | 4.3 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBeAg Loss at Week 24 | 0.0 percentage of participants |
Secondary
Percentage of Participants With HBeAg Loss at Week 48
HBeAg loss was defined as qualitative HBeAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set with HBeAg positive at baseline were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBeAg Loss at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBeAg Loss at Week 48 | 4.5 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBeAg Loss at Week 48 | 8.7 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBeAg Loss at Week 48 | 9.5 percentage of participants |
Secondary
Percentage of Participants With HBsAg Loss at Week 24
HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 24
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBsAg Loss at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBsAg Loss at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBsAg Loss at Week 24 | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBsAg Loss at Week 24 | 0.0 percentage of participants |
Secondary
Percentage of Participants With HBsAg Loss at Week 48
HBsAg loss was defined as qualitative HBsAg test changing from positive at baseline to negative at any postbaseline visit within the targeted time window.
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set were analyzed. The missing equals failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBsAg Loss at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBsAg Loss at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBsAg Loss at Week 48 | 0.0 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBsAg Loss at Week 48 | 0.0 percentage of participants |
Secondary
Percentage of Participants With HBV DNA < LLOQ at Week 48
The LLOQ was defined as 20 IU/mL.
Time frame: Week 48
Population: Participants in the Full Analysis Set with available data were analyzed. The missing equals excluded approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBV DNA < LLOQ at Week 48 | 70.4 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBV DNA < LLOQ at Week 48 | 69.6 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBV DNA < LLOQ at Week 48 | 69.2 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBV DNA < LLOQ at Week 48 | 76.4 percentage of participants |
Secondary
Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24
The LLOQ was defined as 20 IU/mL.
Time frame: Week 24
Population: Participants in the Full Analysis Set with available data were analyzed. The missing equals excluded approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TDF 48 Weeks | Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | 50.0 percentage of participants |
| TDF + GS-4774 2 YU | Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | 58.9 percentage of participants |
| TDF + GS-4774 10 YU | Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | 58.5 percentage of participants |
| TDF + GS-4774 40 YU | Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | 63.6 percentage of participants |