Chronic Hepatitis B
Conditions
Brief summary
The primary objectives of this study are to evaluate the safety, tolerability, and efficacy of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF)-containing regimens at Week 24 in participants with chronic hepatitis B virus (HBV) infection and Stage 2 or greater chronic kidney disease who have received a liver transplant.
Interventions
DRUGTAF
Tablet administered orally
DRUGTDF
Tablet administered orally
DRUGOther approved antivirals
Other approved antivirals (such as lamivudine, entecavir, or immunoglobulin antihepatitis B) administered per local practice
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; consent must be obtained prior to initiation of study procedures * Documented evidence of chronic HBV infection prior to transplantation * Primary or secondary (re-transplant), liver alone or liver and kidney transplant recipient from deceased or living donor * Liver Transplant ≥ 12 weeks prior to screening * Maintained on TDF alone or in combination with other approved antivirals for HBV prophylaxis or treatment * Have been on approved HBV oral antiviral (OAV) treatment for at least 12 weeks post-transplant prior to screening, with HBV DNA \< lower limit of quantification (LLOQ) at screening * Screening estimated glomerular filtration rate using the chronic kidney disease epidemiology collaboration (eGFR\_CKD-EPI) \< 90 ml/min/1.73m\^2 * Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception * Women considered of child bearing potential must have a negative serum pregnancy test at Screening and a negative urine test at Baseline before dosing * Must be willing and able to comply with all study requirements Key
Exclusion criteria
* Multi-organ transplant that includes heart or lung recipient (participants who have their liver transplant as part of a liver-kidney dual transplant are eligible to enroll) * Participants with history of de novo or recurrent hepatocellular carcinoma (HCC) post-transplant and at screening * Histological evidence of unresolved transplant rejection * Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, or other signs of decompensated cirrhosis * Participants meeting any of the following laboratory parameters at screening: * Alanine aminotransferase (ALT) \> 10 × the upper limit of normal (ULN) * International normalized ratio (INR) \> 1.5 × ULN unless the participant is stable on anticoagulant regimen affecting INR * Albumin \< 3.0 g/dL * Direct bilirubin ≥ 4 × ULN * Platelet count \< 50,000/mL * Co-infection with HIV or hepatitis C virus (HCV) * Recent (within 4 weeks of Screening) episode or infection requiring systemic antibiotics * Use of any prohibited medications listed within 28 days of the Baseline/Day 1 visit * Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (e.g., basal cell skin cancer, etc.) or hepatocellular carcinoma. Participants under evaluation for possible malignancy are not eligible * Significant cardiovascular, pulmonary, or neurological disease * Use of investigational agents within 3 months of screening, unless allowed by the Sponsor * Use of any prohibited medications * Current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance * Known hypersensitivity to study drugs, metabolites or formulation excipients * Lactating females or those who may wish to become pregnant during the course of the study NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Serum Estimated Glomerular Filtration Rate (eGFR) at Week 24 Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation | Baseline, Week 24 |
| Percentage of Participants With HBV DNA < 20 IU/mL at Week 24 | Week 24 |
Secondary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline in Spine BMD at Week 24 | Baseline, Week 24 |
| Percent Change From Baseline in Spine BMD at Week 48 | Baseline, Week 48 |
| Change From Baseline in Serum Creatinine at Week 24 | Baseline, Week 24 |
| Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24 | Baseline, Week 24 |
| Change From Baseline in Serum eGFR_CKD-EPI at Week 48 | Baseline, Week 48 |
| Percentage of Participants With HBV DNA < 20 IU/mL at Week 48 | Week 48 |
| Change From Baseline in Serum Creatinine at Week 48 | Baseline, Week 48 |
| Percent Change From Baseline in Hip BMD at Week 48 | Baseline, Week 48 |
Countries
New Zealand
Participant flow
Recruitment details
Participants were enrolled at a study site in New Zealand. The first participant was screened on 16 September 2016. The last study visit occurred on 05 May 2021.
Pre-assignment details
57 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| TAF 25 mg Randomized Phase: TAF 25 mg tablet orally once daily for 48 weeks
OLE Phase: TAF 25 mg tablet orally once daily for additional 144 weeks | 26 |
| TDF-Containing Regimens Randomized Phase: TDF alone or in combination with other approved antivirals per local practice for 48 weeks
OLE Phase: TAF 25 mg tablet orally once daily for additional 144 weeks | 25 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| OLE Phase (Week 49 to Week 192) | Adverse Event | 1 | 0 |
| OLE Phase (Week 49 to Week 192) | Death | 2 | 0 |
| OLE Phase (Week 49 to Week 192) | Withdrew Consent | 0 | 1 |
| Randomized Phase (Up to Week 48) | Death | 0 | 1 |
Baseline characteristics
| Characteristic | TAF 25 mg | Total | TDF-Containing Regimens |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 12.6 | 60 years STANDARD_DEVIATION 10.8 | 62 years STANDARD_DEVIATION 8.3 |
| eGFR by CKD-EPI Creatinine | 52.3 mL/minute/1.73 square meter(m^2) STANDARD_DEVIATION 12.31 | 52.4 mL/minute/1.73 square meter(m^2) STANDARD_DEVIATION 12.4 | 52.4 mL/minute/1.73 square meter(m^2) STANDARD_DEVIATION 12.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants | 51 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HBV Deoxy Ribonucleic Acid (DNA) | 19.0 International unit per mL (IU/mL) STANDARD_DEVIATION 0 | 19.0 International unit per mL (IU/mL) STANDARD_DEVIATION 0 | 19.0 International unit per mL (IU/mL) STANDARD_DEVIATION 0 |
| Race/Ethnicity, Customized Race Asian | 7 Participants | 17 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 15 Participants | 27 Participants | 12 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 2 Participants | 5 Participants | 3 Participants |
| Region of Enrollment New Zealand | 26 Participants | 51 Participants | 25 Participants |
| Sex: Female, Male Female | 10 Participants | 13 Participants | 3 Participants |
| Sex: Female, Male Male | 16 Participants | 38 Participants | 22 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 / 26 | 1 / 25 | 2 / 26 | 0 / 24 |
| other Total, other adverse events | 19 / 26 | 17 / 25 | 22 / 26 | 21 / 24 |
| serious Total, serious adverse events | 3 / 26 | 7 / 25 | 8 / 26 | 8 / 24 |
Outcome results
Primary
Change From Baseline in Serum Estimated Glomerular Filtration Rate (eGFR) at Week 24 Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation
Time frame: Baseline, Week 24
Population: Safety Analysis Set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Change From Baseline in Serum Estimated Glomerular Filtration Rate (eGFR) at Week 24 Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation | 2.13 mL/min/1.73 m^2 | Standard Deviation 6.011 |
| TDF-Containing Regimens | Change From Baseline in Serum Estimated Glomerular Filtration Rate (eGFR) at Week 24 Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine Equation | 1.87 mL/min/1.73 m^2 | Standard Deviation 6.553 |
Primary
Percentage of Participants With HBV DNA < 20 IU/mL at Week 24
Time frame: Week 24
Population: Full Analysis Set included all randomized participants who have received at least 1 dose of study drug. The missing = failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAF 25 mg | Percentage of Participants With HBV DNA < 20 IU/mL at Week 24 | 100.0 percentage of participants |
| TDF-Containing Regimens | Percentage of Participants With HBV DNA < 20 IU/mL at Week 24 | 100.0 percentage of participants |
Secondary
Change From Baseline in Serum Creatinine at Week 24
Time frame: Baseline, Week 24
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Change From Baseline in Serum Creatinine at Week 24 | -0.043 mg/dL | Standard Deviation 0.1434 |
| TDF-Containing Regimens | Change From Baseline in Serum Creatinine at Week 24 | -0.040 mg/dL | Standard Deviation 0.1623 |
Secondary
Change From Baseline in Serum Creatinine at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Change From Baseline in Serum Creatinine at Week 48 | -0.052 mg/dL | Standard Deviation 0.2233 |
| TDF-Containing Regimens | Change From Baseline in Serum Creatinine at Week 48 | -0.058 mg/dL | Standard Deviation 0.2158 |
Secondary
Change From Baseline in Serum eGFR_CKD-EPI at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Change From Baseline in Serum eGFR_CKD-EPI at Week 48 | 3.01 mL/min/1.73 m^2 | Standard Deviation 9.385 |
| TDF-Containing Regimens | Change From Baseline in Serum eGFR_CKD-EPI at Week 48 | 2.09 mL/min/1.73 m^2 | Standard Deviation 9.209 |
Secondary
Percentage of Participants With HBV DNA < 20 IU/mL at Week 48
Time frame: Week 48
Population: Participants in the Full Analysis Set were analyzed. The missing = failure approach was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAF 25 mg | Percentage of Participants With HBV DNA < 20 IU/mL at Week 48 | 100.0 percentage of participants |
| TDF-Containing Regimens | Percentage of Participants With HBV DNA < 20 IU/mL at Week 48 | 88.0 percentage of participants |
Secondary
Percent Change From Baseline in Hip BMD at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Hip DXA Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Hip BMD at Week 48 | 1.253 percent change | Standard Deviation 1.9774 |
| TDF-Containing Regimens | Percent Change From Baseline in Hip BMD at Week 48 | -0.413 percent change | Standard Deviation 2.6361 |
Secondary
Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24
Time frame: Baseline, Week 24
Population: Hip dual energy x-ray absorptiometry (DXA) Analysis Set included participants who were randomized and had received at least 1 dose of study drug, and had nonmissing baseline hip BMD values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24 | 0.478 percent change | Standard Deviation 1.6342 |
| TDF-Containing Regimens | Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 24 | 0.452 percent change | Standard Deviation 2.138 |
Secondary
Percent Change From Baseline in Spine BMD at Week 24
Time frame: Baseline, Week 24
Population: Spine DXA Analysis Set included participants who were randomized and had received at least 1 dose of study drug, and had nonmissing baseline spine BMD values.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Spine BMD at Week 24 | 0.799 percent change | Standard Deviation 2.5563 |
| TDF-Containing Regimens | Percent Change From Baseline in Spine BMD at Week 24 | -0.188 percent change | Standard Deviation 2.589 |
Secondary
Percent Change From Baseline in Spine BMD at Week 48
Time frame: Baseline, Week 48
Population: Participants in the Spine DXA Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TAF 25 mg | Percent Change From Baseline in Spine BMD at Week 48 | 1.454 percent change | Standard Deviation 4.5405 |
| TDF-Containing Regimens | Percent Change From Baseline in Spine BMD at Week 48 | -1.082 percent change | Standard Deviation 3.0031 |