Hepatitis B, Chronic
Conditions
Brief summary
This open-label, randomized, parallel-arm study will assess the early immunologic response in treatment-naïve Asian male patients with chronic hepatitis B after initiation of treatment with Pegasys or tenofovir or Pegasys plus tenofovir. Patients will be randomized to one of 4 cohorts to receive either Pegasys (360mcg subcutaneously weekly) or tenofovir (300mg orally daily) or both or no treatment for 2 weeks. After 2 weeks on study treatment, patients may opt to receive standard of care treatment with Pegasys. Target sample size is \<50.
Interventions
DRUGpeginterferon alfa-2a [Pegasys]
360 micrograms sc/week for 2 weeks
DRUGtenofovir
300mg po daily for 2 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* male adults of Southeast and/or East Asian origin, 18-55 years of age * HBeAg-positive chronic hepatitis B * detectable HBV DNA
Exclusion criteria
* prior antiviral therapy for chronic hepatitis B * evidence of bridging fibrosis, cirrhosis or decompensated liver disease * positive test at screening for HAV (IgM), HCV, HDV or HIV * history or evidence of medical condition associated with chronic liver disease * antineoplastic or immunomodulatory treatment \</=6 months prior to first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Viral Quantitative e Antibody | Day 1, 3, 5, 8, 10, 14, Week 3, 4, 5, 6 (weeks are computed from the first dose of Pegasys) | An acute virologic response was determined by change from baseline in viral antigen/antibody laboratory data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in HBV-DNA log10 | Day 1, 3, 5, 8, 10, 14, Week 3, 4, 5, 6 (weeks are computed from the first dose of Pegasys) | An acute virologic response was determined by change from baseline in HBV-DNA log10. |
| Early Changes in Viral Sequence Associated With Viral Suppression | Day 1, 5, 14, Week 4 and 6 | Viral sequence data was obtained from the first 10 participants enrolled in Study but on analysis of the data, numerous low frequency deviations from the HBV consensus sequences were observed in the 454 SLX sequence data which were not replicated in data obtained from routine Sanger sequencing. These sequence deviations did not correspond to a temporal pattern consistent with selection of mutations following HBV treatment. Moreover, they could not be reliably distinguished from sequencing artifacts. It was also revealed that complete genome coverage was not obtained due to errors in the design of the primer sequences. For these reasons, further sequence analyses were not performed for the remaining treatment population. |
Countries
New Zealand, Singapore, Taiwan, United States
Participant flow
Recruitment details
The study was conducted between 30 July 2009 to 01 February 2012 and recruited participants from 4 centers in New Zealand (1), Taiwan (1), and Singapore (2).
Pre-assignment details
A total of 65 participants were screened of which 30 participants were randomized. 35 participants failed the screening evaluation mainly due to inability to meet the inclusion criteria and consent withdrawal.
Participants by arm
| Arm | Count |
|---|---|
| Tenofovir 300 mg Each participant received Tenofovir 300 mg once a day for 2 weeks and thereafter received an optional treatment of Peginterferon alfa-2a (PEG-IFN alfa-2a) 180 µg after 2 weeks of initial treatment. | 6 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg Each participant received Tenofovir 300 mg once a day and Peginterferon alfa-2a (PEG-IFN alfa-2a), 360 micrograms (µg) subcutaneously once a week for 2 weeks and thereafter received an optional treatment of Peginterferon alfa-2a (PEG-IFN alfa-2a) 180 µg after 2 weeks of initial treatment. | 6 |
| PEG-IFN Alfa-2a 360 μg Each participant received Peginterferon alfa-2a, 360 µg subcutaneously once a week for 2 weeks and thereafter received an optional treatment of Peginterferon alfa-2a (PEG-IFN alfa-2a) 180 µg after 2 weeks of initial treatment. | 12 |
| Delayed Treatment Each participant received PEG-IFN alfa-2a, 360 μg/week after an initial 2-week delay. | 6 |
| Total | 30 |
Baseline characteristics
| Characteristic | Tenofovir 300 mg | Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | PEG-IFN Alfa-2a 360 μg | Delayed Treatment | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 12 Participants | 6 Participants | 30 Participants |
| Age, Continuous | 37.8 years STANDARD_DEVIATION 11.09 | 28 years STANDARD_DEVIATION 3.16 | 28.5 years STANDARD_DEVIATION 5.4 | 27.2 years STANDARD_DEVIATION 3.87 | 30 years STANDARD_DEVIATION 7.26 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants | 6 Participants | 30 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 12 / 12 | 6 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 6 |
Outcome results
Primary
Mean Change From Baseline in Viral Quantitative e Antibody
An acute virologic response was determined by change from baseline in viral antigen/antibody laboratory data.
Time frame: Day 1, 3, 5, 8, 10, 14, Week 3, 4, 5, 6 (weeks are computed from the first dose of Pegasys)
Population: All participants who received at least 1 dose of the study medication were included in this analysis. Only participants with both a baseline value and a value particular time point were summarized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 10 | -0.13 Cut-off index (C.O.I.) | Standard Deviation 0.146 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 8 | -0.05 Cut-off index (C.O.I.) | Standard Deviation 0.051 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 6 | NA Cut-off index (C.O.I.) | — |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 3 | 0.00 Cut-off index (C.O.I.) | Standard Deviation 0.089 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 1 | 0.07 Cut-off index (C.O.I.) | Standard Deviation 0.162 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 4 | -0.04 Cut-off index (C.O.I.) | Standard Deviation 0.302 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 3 | NA Cut-off index (C.O.I.) | — |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 5 | -0.02 Cut-off index (C.O.I.) | Standard Deviation 0.049 |
| Tenofovir 300 mg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 14 | -0.02 Cut-off index (C.O.I.) | Standard Deviation 0.147 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 6 | -0.21 Cut-off index (C.O.I.) | Standard Deviation 0.785 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 3 | 0.03 Cut-off index (C.O.I.) | Standard Deviation 0.267 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 1 | 0.15 Cut-off index (C.O.I.) | Standard Deviation 0.234 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 5 | 0.04 Cut-off index (C.O.I.) | Standard Deviation 0.255 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 8 | 0.07 Cut-off index (C.O.I.) | Standard Deviation 0.223 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 10 | 0.04 Cut-off index (C.O.I.) | Standard Deviation 0.247 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 14 | 0.03 Cut-off index (C.O.I.) | Standard Deviation 0.259 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 3 | 0.01 Cut-off index (C.O.I.) | Standard Deviation 0.219 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 4 | -0.05 Cut-off index (C.O.I.) | Standard Deviation 0.37 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 8 | -0.09 Cut-off index (C.O.I.) | Standard Deviation 0.155 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 4 | -0.29 Cut-off index (C.O.I.) | Standard Deviation 0.322 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 10 | -0.12 Cut-off index (C.O.I.) | Standard Deviation 0.175 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 14 | -0.13 Cut-off index (C.O.I.) | Standard Deviation 0.267 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 3 | -0.22 Cut-off index (C.O.I.) | Standard Deviation 0.282 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 3 | -0.13 Cut-off index (C.O.I.) | Standard Deviation 0.119 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 5 | -0.15 Cut-off index (C.O.I.) | Standard Deviation 0.15 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Week 6 | -0.31 Cut-off index (C.O.I.) | Standard Deviation 0.481 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in Viral Quantitative e Antibody | Day 1 | 0.02 Cut-off index (C.O.I.) | Standard Deviation 0.063 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 3 | -0.10 Cut-off index (C.O.I.) | Standard Deviation 0.274 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Week 3 | NA Cut-off index (C.O.I.) | — |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 1 | 0.03 Cut-off index (C.O.I.) | Standard Deviation 0.062 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Week 6 | NA Cut-off index (C.O.I.) | — |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 10 | 0.03 Cut-off index (C.O.I.) | Standard Deviation 0.127 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 8 | 0.04 Cut-off index (C.O.I.) | Standard Deviation 0.069 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Week 4 | -0.40 Cut-off index (C.O.I.) | Standard Deviation 0.521 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 5 | 0.07 Cut-off index (C.O.I.) | Standard Deviation 0.066 |
| Delayed Treatment | Mean Change From Baseline in Viral Quantitative e Antibody | Day 14 | -0.00 Cut-off index (C.O.I.) | Standard Deviation 0.162 |
Secondary
Early Changes in Viral Sequence Associated With Viral Suppression
Viral sequence data was obtained from the first 10 participants enrolled in Study but on analysis of the data, numerous low frequency deviations from the HBV consensus sequences were observed in the 454 SLX sequence data which were not replicated in data obtained from routine Sanger sequencing. These sequence deviations did not correspond to a temporal pattern consistent with selection of mutations following HBV treatment. Moreover, they could not be reliably distinguished from sequencing artifacts. It was also revealed that complete genome coverage was not obtained due to errors in the design of the primer sequences. For these reasons, further sequence analyses were not performed for the remaining treatment population.
Time frame: Day 1, 5, 14, Week 4 and 6
Secondary
Mean Change From Baseline in HBV-DNA log10
An acute virologic response was determined by change from baseline in HBV-DNA log10.
Time frame: Day 1, 3, 5, 8, 10, 14, Week 3, 4, 5, 6 (weeks are computed from the first dose of Pegasys)
Population: All participants who received at least 1 dose of the study medication were included in this analysis. Only participants with both a baseline value and a value particular time point were summarized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Week 6 | NA IU/mL | — |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Week 3 | -0.76 IU/mL | Standard Deviation 0.518 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 10 | -2.37 IU/mL | Standard Deviation 0.167 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 2 | -0.61 IU/mL | Standard Deviation 0.33 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 14 | -2.7 IU/mL | Standard Deviation 0.142 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Week 5 | NA IU/mL | — |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 3 | -1.04 IU/mL | Standard Deviation 0.342 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Week 4 | -0.84 IU/mL | Standard Deviation 0.422 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 5 | -1.53 IU/mL | Standard Deviation 0.306 |
| Tenofovir 300 mg | Mean Change From Baseline in HBV-DNA log10 | Day 8 | -2.16 IU/mL | Standard Deviation 0.244 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 6 | -1.73 IU/mL | Standard Deviation 1.462 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 3 | -0.75 IU/mL | Standard Deviation 0.48 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 5 | -1.37 IU/mL | Standard Deviation 0.923 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 10 | -2.11 IU/mL | Standard Deviation 0.735 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 3 | -2.88 IU/mL | Standard Deviation 0.702 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 14 | -2.46 IU/mL | Standard Deviation 0.8 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 8 | -1.93 IU/mL | Standard Deviation 0.645 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 2 | -0.46 IU/mL | Standard Deviation 0.196 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 5 | -1.45 IU/mL | Standard Deviation 0.551 |
| Tenofovir 300 mg + PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 4 | -1.49 IU/mL | Standard Deviation 0.652 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 8 | -0.54 IU/mL | Standard Deviation 0.226 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 4 | -0.98 IU/mL | Standard Deviation 0.772 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 2 | -0.14 IU/mL | Standard Deviation 0.179 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 3 | -0.46 IU/mL | Standard Deviation 0.222 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 5 | -0.64 IU/mL | Standard Deviation 0.239 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 6 | -1.30 IU/mL | Standard Deviation 0.978 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 10 | -0.57 IU/mL | Standard Deviation 0.299 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Day 14 | -0.61 IU/mL | Standard Deviation 0.521 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 3 | -0.79 IU/mL | Standard Deviation 0.622 |
| PEG-IFN Alfa-2a 360 μg | Mean Change From Baseline in HBV-DNA log10 | Week 5 | -1.22 IU/mL | Standard Deviation 0.819 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 8 | -0.07 IU/mL | Standard Deviation 0.316 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 5 | -0.06 IU/mL | Standard Deviation 0.12 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Week 4 | -2.17 IU/mL | Standard Deviation 0.871 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Week 3 | -1.80 IU/mL | Standard Deviation 0.866 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 3 | 0.04 IU/mL | Standard Deviation 0.064 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 2 | 0.08 IU/mL | Standard Deviation 0.11 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Week 6 | NA IU/mL | — |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 10 | -0.09 IU/mL | Standard Deviation 0.493 |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Week 5 | NA IU/mL | — |
| Delayed Treatment | Mean Change From Baseline in HBV-DNA log10 | Day 14 | -0.26 IU/mL | Standard Deviation 0.573 |