Study to Evaluate the Safety, Tolerability, and Efficacy of Vesatolimod in Combination With Tenofovir Disoproxil Fumarate (TDF) in Adults With Chronic Hepatitis B (CHB) Infection Who Are Currently Not Being Treated
- Registration Number
- NCT02579382
- Lead Sponsor
- Gilead Sciences
- Brief Summary
The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of vesatolimod (formerly GS-9620) in adults with chronic hepatitis B (CHB) infection who are currently not being treated.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 192
- Adult males or females between the ages of 18-65
- Chronic hepatitis B virus (HBV) infection
- HBV deoxyribonucleic acid (DNA ) ≥ 2000 IU/mL at screening
Key
- Extensive bridging fibrosis or cirrhosis
- Received oral antiviral treatment for HBV or prolonged therapy with immune-modulators or biologics within 3 months of screening
- Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV) or hepatitis D virus (HDV)
- Chronic liver disease other than HBV
- Lactating or pregnant females or those that wish to become pregnant during the course of the study
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description TDF + placebo TDF Main Study Phase: Tenofovir disoproxil fumarate (TDF) 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + placebo Placebo Main Study Phase: Tenofovir disoproxil fumarate (TDF) 300 mg tablets orally once daily for up to 48 weeks + placebo administered orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 1 mg TDF Main Study Phase:TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 1 mg Vesatolimod Main Study Phase:TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 1 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 2 mg Vesatolimod Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 2 mg TDF Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 2 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 4 mg TDF Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144. TDF + Vesatolimod 4 mg Vesatolimod Main Study Phase: TDF 300 mg tablets orally once daily for up to 48 weeks + vesatolimod 4 mg tablet orally once a week (every 7 days) for 12 doses. Optional Treatment Extension Phase: At Week 48 participants had the option to continue TDF 300 mg tablets orally once daily up to Week 144.
- Primary Outcome Measures
Name Time Method Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24 Baseline; Week 24 The change from baseline to Week 24 in HBsAg (log10 IU/mL) was analyzed using a mixed model for repeated measures (MMRM). The model included treatment, baseline HBsAg (log10 IU/mL), baseline Hepatitis B Envelope Antigen (HBeAg) status (positive or negative), baseline alanine aminotransferase (ALT) level relative to upper limit of normal (ULN) (\> 19 vs ≤ 19 IU/L for females; \> 30 vs ≤ 30 IU/L for males), visit and treatment-by-visit interaction as fixed effects, and visit as a repeated measure.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With HBeAg Loss and Seroconversion at Week 48 Week 48 HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative HBeAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
Percentage of Participants With HBsAg Loss and Seroconversion at Week 24 Week 24 HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative Hepatitis B Surface Antibody (HBsAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
Percentage of Participants With HBeAg Loss and Seroconversion at Week 24 Week 24 HBeAg loss was defined as qualitative HBeAg result changing from positive at baseline to negative at any postbaseline visit. HBeAg seroconversion was defined as qualitative Hepatitis B Envelope Antibody (HBeAb) result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 48 Baseline; Week 48 Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 12 Baseline to Week 12 HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures.
Percentage of Participants With Hepatitis B Virus Deoxyribonucleic Acid (HBV DNA) < Lower Limit of Quantitation (LLOQ) at Week 24 Week 24 LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis.
Percentage of Participants With HBV DNA < LLOQ at Week 48 Week 48 LLOQ for HBV DNA was defined as 20 IU/mL. The participants with missing information were excluded from the analysis.
Number of Participants With Sequence Changes From Baseline Within the HBV Polymerase/Reverse Transcriptase (Pol/RT) Baseline; Week 48 Sequence analysis of the HBV pol/RT was attempted for any participant who had HBV DNA ≥ 69 IU/mL at Week 48 or early discontinuation. Results of the alignment of Week 48 and baseline sequence were reported as a change from baseline sequence.
Pharmacokinetic (PK) Parameter: AUClast of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose AUClast is defined as the area under the concentration versus time curve from time zero to the last quantifiable concentration.
Percentage of Participants With HBsAg Loss and Seroconversion at Week 48 Week 48 HBsAg loss was defined as qualitative HBsAg result changing from positive at baseline to negative at any postbaseline visit. HBsAg seroconversion was defined as qualitative HBsAb result changing from negative at baseline to positive at any postbaseline visit. The Missing (M) = Failure (F) approach was used for this analysis.
Mean Change (Measured in log10 IU/mL) in HBsAg From Baseline at Week 12 Baseline; Week 12 Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 24 Baseline to Week 24 HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 24 post-baseline visit.
Percentage of Participants With a ≥ 0.5 log10 IU/mL Decline in Serum HBsAg Titers From Baseline at Week 48 Baseline to Week 48 HBsAg ≥ 0.5 log10 IU/mL decline was defined as a decline from baseline in log10 IU/mL serum HBsAg ≥ 0.5 at the Week 12 post-baseline visit. Missing values were considered failures.
Percentage of Participants Experiencing Virologic Breakthrough Weeks 24 and 48 Virologic breakthrough was defined as confirmed HBV DNA ≥ 69 IU/mL after having had HBV DNA \< 69 IU/mL or confirmed 1.0 log10 IU/mL or greater increase in HBV DNA from nadir. Confirmation requires 2 consecutive occurrences of elevation in HBV DNA to \> 69 IU/mL after having had HBV DNA \< 69 IU/mL or 1.0 log10 IU/mL or greater increases in HBV DNA from nadir.
PK Parameter: AUCinf of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose AUCinf is defined as the concentration of drug extrapolated to infinite time.
PK Parameter: %AUCexp of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf.
PK Parameter: Cmax of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose Cmax is defined as the maximum concentration of drug.
PK Parameter: Clast of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose Clast is defined as the last observable concentration of drug.
PK Parameter: Tmax of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose Tmax is defined as the time (observed time point) of Cmax
PK Parameter: Tlast of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose Tlast is defined as the time (observed time point) of Clast.
PK Parameter: T1/2 of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose T1/2 is defined as the estimate of the terminal elimination half-life of the drug.
PK Parameter: CL/F of Vesatolimod Week 11: Predose, 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours postdose CL/F is defined as the apparent oral clearance following administration of the drug.