Safety and Efficacy of GS-4774 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Participants With Chronic Hepatitis B (CHB) and Who Are Currently Not on Treatment

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Randomized, Open-Label Study to Evaluate the Safety and Efficacy of GS-4774 in Combination With Tenofovir Disoproxil Fumarate (TDF) for the Treatment of Subjects With Chronic Hepatitis B and Who Are Currently Not on Treatment

Conditions
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Chronic Hepatitis B

Intervention / Treatment
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* Drug: Tenofovir disoproxil fumarate
* Biological: GS-4774


Participation Criteria
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Eligibility Criteria
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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/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: TDF 48 weeks<br>Participants will receive TDF for 48 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks. | Drug: Tenofovir disoproxil fumarate<br>* TDF 300 mg tablet administered orally once daily<br>* Other names: Viread®;|
| Experimental: TDF plus GS-4774 2 YU<br>Participants will receive TDF plus GS-4774 2 yeast units (YU) for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks. | Drug: Tenofovir disoproxil fumarate<br>* TDF 300 mg tablet administered orally once daily<br>* Other names: Viread®;Biological: GS-4774<br>* GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses<br>|
| Experimental: TDF plus GS-4774 10 YU<br>Participants will receive TDF plus GS-4774 10 YU for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks. | Drug: Tenofovir disoproxil fumarate<br>* TDF 300 mg tablet administered orally once daily<br>* Other names: Viread®;Biological: GS-4774<br>* GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses<br>|
| Experimental: TDF plus GS-4774 40 YU<br>Participants will receive TDF plus GS-4774 40 YU for 20 weeks. After Week 20, GS-4774 will be discontinued and participants will continue on TDF for an additional 28 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks. | Drug: Tenofovir disoproxil fumarate<br>* TDF 300 mg tablet administered orally once daily<br>* Other names: Viread®;Biological: GS-4774<br>* GS-4774 subcutaneous injection administered every 4 weeks for a total of 6 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 12 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 | The LLOQ was defined as 20 IU/mL. | Week 24 | 
| Percentage of Participants With HBV DNA < LLOQ at Week 48 | The LLOQ was defined as 20 IU/mL. | Week 48 | 
| 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. | Baseline to Week 24 | 
| 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. | Baseline to Week 48 | 
| 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. | Baseline to Week 48 |