Hepatitis B, Chronic
Conditions
Brief summary
This 2 arm study will assess the efficacy and safety of Pegasys in combination or sequential treatment with entecavir in patients with HBeAg positive chronic hepatitis B. Patients who have been pretreated with, and responded to, entecavir for 9 to 36 months were randomized to one of 2 groups, to receive Pegasys 180micrograms/week sc for 48 weeks + entecavir 0.5mg po daily for 8 weeks, or entecavir 0.5mg po daily for 48 weeks. The anticipated time on study treatment is 3-12 months.
Interventions
DRUGentecavir
0.5mg po daily for 8 weeks
DRUGpeginterferon alfa-2a [Pegasys]
180 micrograms sc/week for 48 weeks
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients, \>=18 and \</= 65 years of age * HBeAg positive chronic hepatitis B * Pre-treatment with entecavir for 9-36 months
Exclusion criteria
* Antiviral, antineoplastic or immunomodulatory treatment * Co-infection with active hepatitis A, C or D, or HIV * Evidence of decompensated liver disease * History or other evidence of a medical condition associated with chronic liver disease other than viral hepatitis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48 | At Week 48 | Hepatitis B envelope Antigen (HBeAg) seroconversion was defined as the absence of HBeAg and the presence of antibody to Hepatitis B envelope antigen (anti-HBe). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48 | At Week 48 | Blood was collected for Hepatitis B Virus - Deoxyribonucleic Acid (HBV -DNA) and was analysed at the central laboratories using the Roche approved polymerase chain reaction (PCR) methodology at Week 48. Percentage of participants with HBV-DNA \< 1000 copies/mL was reported. |
| Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48 | At Week 48 | Loss of Hepatitis B Surface Antigen (HBsAg) was defined as change of detectable HBsAg from positive to negative. |
| Percentage of Participants With Hepatitis B Surface Antigen Seroconversion at Week 48 | At Week 48 | Hepatitis B Surface Antigen (HBsAg) seroconversion was defined as loss of HBsAg and presence of anti-HBs .(antibody to Hepatitis B surface antigen) |
| Percentage of Participants With Normalized Alanine Aminotransferase at Week 48 | At Week 48 | Normalized Alanine Aminotransferase (ALT) is defined as having a baseline ALT value \> upper limit of normal (ULN), and a decrease in ALT value to ≤ ULN at the given time point. |
| Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48 | At Week 48 | Loss of Hepatitis B Envelope Antigen (HBeAg) is defined as the absence of HBeAg. |
| Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | Up to Week 48 | Quantitative Hepatitis B Surface Antigen (HBsAg) results were analyzed in central lab. Values that were less than LLOQ had been replaced by LLOQ when analyzed, e.g. \<1000 was replaced by 1000 and \<0.2 was replaced by 0.2. Quantitative HBsAg calculated using 'International Units Per Millilitre' (IU/mL). Change in HBsAg was analysed at Weeks 0, 8, 12, 24, 36, and 48. |
| Number of Participants With Incidence of Adverse Events and Serious Adverse Events | Up to Week 48 | An adverse event (AE) was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Events (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect. |
| Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Up to Week 48 | Participants with clinically significant laboratory abnormalities which were captured as an AE (at the \>=5% threshold) were presented. |
| Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | Up to Week 48 | Quantitative hepatitis B envelope antigen (HBeAg) results were analyzed in central lab. Values that were less than lower limit of quantification (LLOQ) had been replaced by LLOQ when analyzed, e.g. \<1000 was replaced by 1000 and \<0.2 was replaced by 0.2. Quantitative HBeAg value unit was calculated using 'Paul Ehrlich Institute units per millilitre' (PEIU/ml). Change in HBeAg was analysed at Weeks 0, 8, 12, 24, 36, and 48. |
Countries
China
Participant flow
Recruitment details
A total of 332 participants were enrolled in this study conducted from 28 April 2009 to 23 December 2011 at seven centers in China.
Pre-assignment details
Of 332 participants, 200 were randomized, out of which 97 participants were assigned to Peginterferon alfa-2a + entecavir and 100 were assigned to entecavir, and three participants did not take any study drug.
Participants by arm
| Arm | Count |
|---|---|
| Peginterferon Alfa-2a + Entecavir Participants received peginterferon alfa-2a180 mcg subcutaneously once weekly for 48 weeks, plus entecavir 0.5 mg orally once daily for 8 weeks. | 94 |
| Entecavir Participants received entecavir 0.5 mg orally once daily for 48 weeks. | 98 |
| Total | 192 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 0 |
| Overall Study | HBeAb positive at Baseline | 3 | 2 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Others | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Peginterferon Alfa-2a + Entecavir | Entecavir | Total |
|---|---|---|---|
| Age, Continuous | 33.38 years STANDARD_DEVIATION 8.25 | 33.28 years STANDARD_DEVIATION 8.95 | 33.3 years STANDARD_DEVIATION 8.6 |
| Sex: Female, Male Female | 19 Participants | 13 Participants | 32 Participants |
| Sex: Female, Male Male | 75 Participants | 85 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 65 / 97 | 5 / 100 |
| serious Total, serious adverse events | 6 / 97 | 0 / 100 |
Outcome results
Primary
Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48
Hepatitis B envelope Antigen (HBeAg) seroconversion was defined as the absence of HBeAg and the presence of antibody to Hepatitis B envelope antigen (anti-HBe).
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48 | 14.89 Percentage of participants |
| Entecavir | Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48 | 6.12 Percentage of participants |
Secondary
Number of Participants With Incidence of Adverse Events and Serious Adverse Events
An adverse event (AE) was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A Serious Adverse Events (SAE) is any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.
Time frame: Up to Week 48
Population: Safety set (SS) included all the participants who received at least 1 dose of study drug and who had at least undergone safety assessment once, regardless of whether the patients withdrew from the study or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | Non serious AE | 65 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | Serious AE | 6 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | AE | 67 Participants |
| Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | Non serious AE | 5 Participants |
| Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | Serious AE | 0 Participants |
| Entecavir | Number of Participants With Incidence of Adverse Events and Serious Adverse Events | AE | 5 Participants |
Secondary
Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event
Participants with clinically significant laboratory abnormalities which were captured as an AE (at the \>=5% threshold) were presented.
Time frame: Up to Week 48
Population: Safety set (SS) included all the participants who received at least 1 dose of study drug and who had at least undergone safety assessment once, regardless of whether the patients withdrew from the study or not.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Platelet count decreased | 42 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Haemoglobin decreased | 6 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Neutrophil count decreased | 53 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Alanine aminotransferase increased | 9 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | White blood cell count decreased | 59 Participants |
| Peginterferon Alfa-2a + Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Aspartate aminotransferase increased | 8 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | White blood cell count decreased | 0 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Aspartate aminotransferase increased | 0 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Alanine aminotransferase increased | 0 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Platelet count decreased | 0 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Neutrophil count decreased | 0 Participants |
| Entecavir | Number of Participants With Laboratory Abnormalities Which Were Captured as an Adverse Event | Haemoglobin decreased | 0 Participants |
Secondary
Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48
Loss of Hepatitis B Surface Antigen (HBsAg) was defined as change of detectable HBsAg from positive to negative.
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48 | 8.51 Percentage of participants |
| Entecavir | Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48 | 0 Percentage of participants |
Secondary
Percentage of Participants With Hepatitis B Surface Antigen Seroconversion at Week 48
Hepatitis B Surface Antigen (HBsAg) seroconversion was defined as loss of HBsAg and presence of anti-HBs .(antibody to Hepatitis B surface antigen)
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Hepatitis B Surface Antigen Seroconversion at Week 48 | 4.26 Percentage of participants |
| Entecavir | Percentage of Participants With Hepatitis B Surface Antigen Seroconversion at Week 48 | 0 Percentage of participants |
Secondary
Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48
Blood was collected for Hepatitis B Virus - Deoxyribonucleic Acid (HBV -DNA) and was analysed at the central laboratories using the Roche approved polymerase chain reaction (PCR) methodology at Week 48. Percentage of participants with HBV-DNA \< 1000 copies/mL was reported.
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48 | 62.77 Percentage of participants |
| Entecavir | Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48 | 91.84 Percentage of participants |
Secondary
Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48
Loss of Hepatitis B Envelope Antigen (HBeAg) is defined as the absence of HBeAg.
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48 | 62.77 Percentage of participants |
| Entecavir | Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48 | 60.20 Percentage of participants |
Secondary
Percentage of Participants With Normalized Alanine Aminotransferase at Week 48
Normalized Alanine Aminotransferase (ALT) is defined as having a baseline ALT value \> upper limit of normal (ULN), and a decrease in ALT value to ≤ ULN at the given time point.
Time frame: At Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Percentage of Participants With Normalized Alanine Aminotransferase at Week 48 | 51.06 Percentage of participants |
| Entecavir | Percentage of Participants With Normalized Alanine Aminotransferase at Week 48 | 85.71 Percentage of participants |
Secondary
Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time
Quantitative hepatitis B envelope antigen (HBeAg) results were analyzed in central lab. Values that were less than lower limit of quantification (LLOQ) had been replaced by LLOQ when analyzed, e.g. \<1000 was replaced by 1000 and \<0.2 was replaced by 0.2. Quantitative HBeAg value unit was calculated using 'Paul Ehrlich Institute units per millilitre' (PEIU/ml). Change in HBeAg was analysed at Weeks 0, 8, 12, 24, 36, and 48.
Time frame: Up to Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug. Maximum participants available at particular time point were analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 0; n= 93, 95 | 8.33 PEIU/ml) | Standard Deviation 18.76 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 8; n= 93, 97 | 4.76 PEIU/ml) | Standard Deviation 11.63 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 12; n= 94, 97 | 3.83 PEIU/ml) | Standard Deviation 10.57 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 24; n= 91, 97 | 2.28 PEIU/ml) | Standard Deviation 5.81 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 36; n= 88, 94 | 3.58 PEIU/ml) | Standard Deviation 16.66 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 48; n= 85, 92 | 13.23 PEIU/ml) | Standard Deviation 93.02 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 36; n= 88, 94 | 4.52 PEIU/ml) | Standard Deviation 10.1 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 0; n= 93, 95 | 5.66 PEIU/ml) | Standard Deviation 10.33 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 24; n= 91, 97 | 4.76 PEIU/ml) | Standard Deviation 11.4 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 8; n= 93, 97 | 5.85 PEIU/ml) | Standard Deviation 12.55 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 48; n= 85, 92 | 4.07 PEIU/ml) | Standard Deviation 9.15 |
| Entecavir | Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time | At Week 12; n= 94, 97 | 5.00 PEIU/ml) | Standard Deviation 10.56 |
Secondary
Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time
Quantitative Hepatitis B Surface Antigen (HBsAg) results were analyzed in central lab. Values that were less than LLOQ had been replaced by LLOQ when analyzed, e.g. \<1000 was replaced by 1000 and \<0.2 was replaced by 0.2. Quantitative HBsAg calculated using 'International Units Per Millilitre' (IU/mL). Change in HBsAg was analysed at Weeks 0, 8, 12, 24, 36, and 48.
Time frame: Up to Week 48
Population: Full analysis set included all patients who were randomized and received at least one dose of the study drug. Maximum participants available at particular time point were analysed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 0; n= 93, 95 | 3737.84 IU/ml | Standard Deviation 4617.19 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 8; n= 93, 97 | 3603.56 IU/ml | Standard Deviation 4553.66 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 12; n= 94, 97 | 3041.86 IU/ml | Standard Deviation 3782.7 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 24; n= 91, 97 | 2280.60 IU/ml | Standard Deviation 3429.61 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 36; n= 88, 94 | 2097.89 IU/ml | Standard Deviation 3458.84 |
| Peginterferon Alfa-2a + Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 48; n= 85, 92 | 1886.02 IU/ml | Standard Deviation 2627.33 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 36; n= 88, 94 | 2699.18 IU/ml | Standard Deviation 2964.25 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 0; n= 93, 95 | 3241.06 IU/ml | Standard Deviation 3592.6 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 24; n= 91, 97 | 2895.25 IU/ml | Standard Deviation 3336.91 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 8; n= 93, 97 | 3050.79 IU/ml | Standard Deviation 3313.12 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 48; n= 85, 92 | 2672.71 IU/ml | Standard Deviation 3065.97 |
| Entecavir | Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time | At Week 12; n= 94, 97 | 3037.82 IU/ml | Standard Deviation 3498.73 |