Chronic Hepatitis B
Conditions
Keywords
Truvada, HBIg, Chronic Hepatitis B Recurrence, Post Orthotopic Liver Transplant
Brief summary
The objective of this 96-week study was to evaluate the safety and antiviral efficacy of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, coformulated; Truvada®) with or without hepatitis B immunoglobulin (HBIg) in preventing the recurrence of chronic hepatitis B following liver transplantation, in participants who were chronically infected with hepatitis B prior to transplantation. Prior to enrollment, participants were required to have received at least 12 weeks of HBIg therapy following liver transplantation. Enrolled participants then received FTC/TDF plus HBIg for an initial 24-week pre-randomization treatment period. Participants who completed the pre-randomization period and who achieved sustained viral suppression were randomized to continue treatment with FTC/TDF with or without HBIg for an additional 72 weeks (randomized period). The antiviral efficacy of treatment was assessed by measuring hepatitis B virus levels in the blood (HBV DNA). Safety and tolerability was monitored by assessing adverse events and various laboratory parameters.
Interventions
DRUGFTC/TDF
Emtricitabine (FTC) 200 mg/tenofovir disoproxil fumarate (TDF) 300 mg was administered as a fixed-dose combination tablet orally once daily.
HBIg was administered either intravenously or by intramuscular injection at a dose and frequency as prescribed by the investigative site protocol.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Adult subjects (18-75 years of age) with either hepatitis e antigen (HBeAg) positive or HBeAg negative chronic HBV prior to transplant * Willing and able to provide written informed consent * Subjects with detectable antibody to hepatitis B surface antigen performed by a local laboratory result within 30 days of screening * Subjects must have been stable and may not have had 2 or more of the following laboratory parameters associated with decompensated liver disease: conjugated bilirubin \> 1.5 x the upper limit of the normal range (ULN), prothrombin time \> 1.5 x ULN, platelets \< 60,000/mm\^3, serum albumin \< 3.0 g/dL * Must have had at least 12 weeks of center-specific prophylactic therapy including hepatitis B immunoglobulin (HBIg) posttransplant * Calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gault equation * No significant evidence of ongoing deterioration of renal function * Negative serum beta-human chorionic gonadotropin (for females of childbearing potential only)
Exclusion criteria
* Subjects with HBV recurrence, ie, confirmed HBV DNA ≥ 400 copies/mL, following liver transplant * Pregnant women, women who were breast feeding or who believed they may have wished to become pregnant during the course of the study * Males and females of reproductive potential who were unwilling to use an effective method of contraception during the study and for at least 30 days from the date of last dose of study drug * Evidence of hepatocellular carcinoma (HCC), eg, alpha-fetoprotein \> 50 ng/mL, or by any other standard of care measure or presence of multifocal HCC at the time of transplantation if transplantation was within 144 weeks of screening * Prior TDF or FTC/TDF experience post-transplant or \> 12 months treatment with TDF or FTC/TDF treatment pretransplant * Coinfection with hepatitis C virus (by serology), HIV, or hepatitis D virus pretransplant or at screening * Significant renal, cardiovascular, pulmonary, or neurological disease * Known hypersensitivity to the study drugs, the metabolites, or formulation excipients * Were likely to receive systemic drugs with nephrotoxic potential, except immunosuppressive agents (eg, cyclosporine, tacrolimus), during the course of the study * History of variceal bleeding or hepatic encephalopathy following orthotopic liver transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HBV Recurrence Prior to or at Week 72 | Pretreatment baseline through Week 72 | HBV recurrence was defined as either HBV DNA ≥ 400 at 2 consecutive visits before Week 72, or HBV DNA ≥ 400 at the Week 72 visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HBV Recurrence at Week 96 | Week 96 | HBV recurrence was defined as HBV DNA ≥ 400 at the Week 96 visit. |
| Percentage of Subjects With HBV DNA < 169 Copies/mL at Week 72 | Week 72 | — |
| Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96 | Week 96 | — |
| Percentage of Participants With Normal ALT at Week 72 | Week 72 | Range of normal ALT was 6 to 34 U/L for females 18-69 years of age, and 6 to 32 U/L for females over age 69. Range of normal ALT was 6 to 43 U/L for males 18-69 years of age, and 6 to 35 U/L for males over age 69. |
| Percentage of Participants With Normal ALT at Week 96 | Week 96 | Range of normal ALT was 6 to 34 U/L for females 18-69 years of age, and 6 to 32 U/L for females over age 69. Range of normal ALT was 6 to 43 U/L for males 18-69 years of age, and 6 to 35 U/L for males over age 69. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at 7 sites in the United States. The first participant was screened on 12 September 2007. The last participant observation was on 03 May 2011.
Pre-assignment details
51 participants were screened; 40 received emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)+HBIg in the pre-randomization period; 37 received FTC/TDF+HBIg or FTC/TDF in the randomized period.
Participants by arm
| Arm | Count |
|---|---|
| FTC/TDF+HBIg For Baseline Characteristics, this group includes participants who received FTC/TDF+HBIg in the pre-randomization period, and were then randomized to receive FTC/TDF+HBIg in the randomized period. FTC (200 mg)/TDF (300 mg) was administered as a fixed-dose combination tablet orally once daily. HBIG was administered according to site-specific protocols. | 19 |
| FTC/TDF For Baseline Characteristics, this group includes participants who received FTC/TDF+HBIg in the pre-randomization period, and were then randomized to receive FTC/TDF in the randomized period. FTC (200 mg)/TDF (300 mg) was administered as a fixed-dose combination tablet orally once daily. HBIG was administered according to site-specific protocols. | 18 |
| Not Randomized For Baseline Characteristics, this group includes participants who received FTC/TDF+HBIg in the pre-randomization period only. FTC (200 mg)/TDF (300 mg) was administered as a fixed-dose combination tablet orally once daily. HBIG was administered according to site-specific protocols. | 3 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-Randomization Period | Adverse Event | 1 | 0 |
| Pre-Randomization Period | Physician Decision | 1 | 0 |
| Pre-Randomization Period | Withdrawal by Subject | 1 | 0 |
| Randomized Period | Adverse Event | 1 | 1 |
| Randomized Period | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | FTC/TDF | Not Randomized | FTC/TDF+HBIg | Total |
|---|---|---|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 9.1 | 64 years STANDARD_DEVIATION 6 | 54 years STANDARD_DEVIATION 9.7 | 57 years STANDARD_DEVIATION 9.6 |
| Baseline alanine aminotransferase (ALT) above the upper limit of the normal range (ULN) ≤ ULN | 16 participants | 3 participants | 19 participants | 38 participants |
| Baseline alanine aminotransferase (ALT) above the upper limit of the normal range (ULN) > ULN | 2 participants | 0 participants | 0 participants | 2 participants |
| Baseline hepatitis B virus (HBV) DNA Below 169 copies/mL < 169 copies/mL | 18 participants | 3 participants | 19 participants | 40 participants |
| Baseline hepatitis B virus (HBV) DNA Below 169 copies/mL ≥ 169 copies/mL | 0 participants | 0 participants | 0 participants | 0 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 3 Participants | 17 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 8 participants | 1 participants | 6 participants | 15 participants |
| Race/Ethnicity, Customized Black | 4 participants | 1 participants | 5 participants | 10 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized White | 5 participants | 1 participants | 7 participants | 13 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 2 Participants | 15 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 40 | 15 / 19 | 11 / 18 |
| serious Total, serious adverse events | 2 / 40 | 6 / 19 | 3 / 18 |
Outcome results
Primary
Percentage of Participants With HBV Recurrence Prior to or at Week 72
HBV recurrence was defined as either HBV DNA ≥ 400 at 2 consecutive visits before Week 72, or HBV DNA ≥ 400 at the Week 72 visit.
Time frame: Pretreatment baseline through Week 72
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Participants With HBV Recurrence Prior to or at Week 72 | 0 percentage of participants |
| FTC/TDF | Percentage of Participants With HBV Recurrence Prior to or at Week 72 | 0 percentage of participants |
Secondary
Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96
Time frame: Week 96
Population: Participants in the Full Analysis Set with available data at Week 96 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96 | 100 percentage of participants |
| FTC/TDF | Percentage of Participants With HBV DNA < 169 Copies/mL at Week 96 | 100 percentage of participants |
Secondary
Percentage of Participants With HBV Recurrence at Week 96
HBV recurrence was defined as HBV DNA ≥ 400 at the Week 96 visit.
Time frame: Week 96
Population: Participants in the Full Analysis Set with available data at Week 96 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Participants With HBV Recurrence at Week 96 | 0 percentage of participants |
| FTC/TDF | Percentage of Participants With HBV Recurrence at Week 96 | 0 percentage of participants |
Secondary
Percentage of Participants With Normal ALT at Week 72
Range of normal ALT was 6 to 34 U/L for females 18-69 years of age, and 6 to 32 U/L for females over age 69. Range of normal ALT was 6 to 43 U/L for males 18-69 years of age, and 6 to 35 U/L for males over age 69.
Time frame: Week 72
Population: Participants in the Full Analysis Set with available data at Week 72 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Participants With Normal ALT at Week 72 | 89 percentage of participants |
| FTC/TDF | Percentage of Participants With Normal ALT at Week 72 | 81 percentage of participants |
Secondary
Percentage of Participants With Normal ALT at Week 96
Range of normal ALT was 6 to 34 U/L for females 18-69 years of age, and 6 to 32 U/L for females over age 69. Range of normal ALT was 6 to 43 U/L for males 18-69 years of age, and 6 to 35 U/L for males over age 69.
Time frame: Week 96
Population: Participants in the Full Analysis Set with available data at Week 96 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Participants With Normal ALT at Week 96 | 88 percentage of participants |
| FTC/TDF | Percentage of Participants With Normal ALT at Week 96 | 80 percentage of participants |
Secondary
Percentage of Subjects With HBV DNA < 169 Copies/mL at Week 72
Time frame: Week 72
Population: Participants in the Full Analysis Set with available data at Week 72 were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/TDF+HBIg | Percentage of Subjects With HBV DNA < 169 Copies/mL at Week 72 | 100 percentage of participants |
| FTC/TDF | Percentage of Subjects With HBV DNA < 169 Copies/mL at Week 72 | 100 percentage of participants |