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
- Conditions
- Chronic Hepatitis B
- Interventions
- Drug: Tenofovir disoproxil fumarateBiological: GS-4774
- Registration Number
- NCT02174276
- Lead Sponsor
- Gilead Sciences
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 195
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TDF plus GS-4774 40 YU GS-4774 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. TDF plus GS-4774 2 YU GS-4774 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. TDF plus GS-4774 10 YU GS-4774 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. TDF 48 weeks Tenofovir disoproxil fumarate Participants will receive TDF for 48 weeks. After Week 48, participants will have the option to continue receiving TDF for up to 144 weeks. TDF plus GS-4774 2 YU Tenofovir disoproxil fumarate 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. TDF plus GS-4774 10 YU Tenofovir disoproxil fumarate 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. TDF plus GS-4774 40 YU Tenofovir disoproxil fumarate 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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.
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.
Percentage of Participants With HBV DNA < Lower Limit of Quantification (LLOQ) at Week 24 Week 24 The LLOQ was defined as 20 IU/mL.
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 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.
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.
Trial Locations
- Locations (31)
Stanford University Medical Center
🇺🇸Palo Alto, California, United States
Kaiser Permanente
🇺🇸Springfield, Virginia, United States
Research and Education, Inc.
🇺🇸San Diego, California, United States
Silicon Valley Research Institute
🇺🇸San Jose, California, United States
Kaiser Permanente San Francisco
🇺🇸San Francisco, California, United States
Digestive Disease Associates, PA
🇺🇸Baltimore, Maryland, United States
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Xiaoli Ma, PC
🇺🇸Philadelphia, Pennsylvania, United States
Gordon & Leslie Diamond Health Care Centre
🇨🇦Vancouver, British Columbia, Canada
Toronto Liver Centre
🇨🇦Toronto, Ontario, Canada
Toronto General Hospital-The University Health Network
🇨🇦Toronto, Ontario, Canada
Toronto Western Hospital-The University Health Network
🇨🇦Toronto, Ontario, Canada
Aou-S.Orsola-Malpighi - Universita Degli Studi Di
🇮🇹Bologna, Italy
Azienda Ospedaliero-Universitaria di Parma
🇮🇹Parma, Italy
Seoul National University Bundang Hospital
🇰🇷Seongnam, Korea, Republic of
The Catholic University of Korea
🇰🇷Yangsan, Korea, Republic of
Kyungpook National University Hospital
🇰🇷Daegu, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Yonsei Universiity
🇰🇷Seoul, Korea, Republic of
Pusan National University Yangsan Hospital
🇰🇷Yangsan, Korea, Republic of
Auckland Clinical Studies
🇳🇿Auckland, New Zealand
Seoul National University College of Medicine
🇰🇷Seoul, Korea, Republic of
Institutul National de Boli Infectioase Prof.Dr. Matei Bals
🇷🇴Bucharest, Romania
Dr. Victor Babes Hospital for Infectious Diseases
🇷🇴Bucharest, Romania
Liver and Intestinal Research Center
🇨🇦Vancouver, British Columbia, Canada
The Queen's Medical Center
🇺🇸Honolulu, Hawaii, United States
Icahn School of Medicine at Mount Sinai
🇺🇸New York, New York, United States
Azienda Ospedaliero-Universitaria Pisana
🇮🇹Pisa, Italy
IRCCS Casa Sollievo della Sofferenza
🇮🇹San Giovanni Rotondo, Italy
University of Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Tufts Medical Center
🇺🇸Boston, Massachusetts, United States