Hepatitis B
Conditions
Keywords
Hepatitis B, Immune-tolerant hepatitis B, HBV
Brief summary
The investigators evaluated the safety and efficacy of a short lead-in course (8 weeks) of entecavir followed by combination of entecavir plus peginterferon alfa-2a for 40 weeks.
Detailed description
To determine the efficacy of treatment with 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon in the treatment of chronic hepatitis B in hepatitis B e antigen (HBeAg) positive adults who are in the immune tolerant phase. To evaluate safety and sustained responses after treatment with entecavir and peginterferon alfa-2a in the treatment of chronic hepatitis B in HBeAg positive adults who are in the immune tolerant phase. A single arm treatment study of 8 weeks of entecavir followed by 40 weeks of both entecavir and peginterferon alfa-2a in adults with HBeAg-positive chronic hepatitis B with normal or near normal alanine aminotransferase (ALT) levels and high serum levels of hepatitis B virus (HBV) DNA (immune tolerant HBeAg-positive chronic hepatitis B). All participants followed for 48 weeks after treatment discontinuation (week 96 for those who completed treatment).
Interventions
Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon 180 µg sq weekly during weeks 9-48 of treatment.
Sponsors
University of Pittsburgh
National Center for Research Resources (NCRR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Enrolled in & completed the baseline evaluation for NCT01263587 or completed the necessary components of NCT01263587 by the end of baseline visit. * \>18 years of age at the baseline visit (day 0). Patients \>50 years of age at baseline will need to have a liver biopsy as standard of care with hepatic activity index (HAI) ≤3 & Ishak fibrosis score ≤1 within 96 weeks prior to baseline visit. * Documented chronic HBV infection as evidenced by detection of HBsAg in serum for ≥24 weeks prior to baseline visit OR at least one positive HBsAg & negative anti-hepatitis B core (HBc) immunoglobulin (IgM) within 24 weeks prior to baseline visit OR at least one positive HBsAg & two positive HBV DNA over a period of ≥24 weeks prior to baseline visit. * Presence of HBeAg in serum at last screening visit within 6 weeks of baseline visit. * Serum HBV DNA level \>10˄7 IU/mL on at least two occasions at least 12 weeks apart during the 52 weeks before baseline visit. One of the two HBV DNA levels must be within 6 weeks of baseline visit. * ALT levels persistently ≤45 U/L in males, ≤30 U/L in females (approx. 1.5 times the upper limit of normal (ULN) range) as documented by at least three values: one taken 28-52 weeks before baseline visit, one taken 6 to 24 weeks before the baseline visit, & the final value within 6 weeks prior to baseline visit. * No evidence of hepatocellular carcinoma (HCC) based upon alpha-fetoprotein (AFP) ≤20 ng/mL at screening visit (up to 6 weeks prior to baseline visit). a. Participants who meet American Association for the Study of Liver Diseases (AASLD) criteria for HCC surveillance must have negative liver imaging as shown by ultrasound, computerized tomography (CT) or magnetic resonance imaging (MRI) within 28 weeks prior to baseline visit. b. Participants with AFP \>20 ng/mL must be evaluated clinically with additional imaging & shown not to have HCC on CT or MRI before they can be enrolled.
Exclusion criteria
* History of hepatic decompensation * Evidence of decompensated liver disease prior to or during screening, including direct bilirubin \>0.5 mg/dL, international normalization ratio (INR) \>1.5, or serum albumin \<3.5 g/dL. * Platelet count \<120,000/mm3, hemoglobin \<13 g/dL (males) or \<12 g/dL (females), absolute neutrophil count \< 1500 /mm3 (\<1000/mm3 for African-Americans) at last screening visit. * Previous treatment with medications that have established activity against HBV including interferon & nucleos(t)ide analogs ≥24 weeks. Patients with \<24 weeks of prior HBV treatment & a wash-out period \>24 weeks are not excluded. * Known allergy or intolerance to study medications. * Females who are pregnant or breastfeeding. Females of childbearing potential unable or unwilling to use a reliable method of contraception during the treatment period. * Renal insufficiency with calculated creatinine clearance \<50 mL/min at screening. * History of alcohol or drug abuse within 48 weeks of baseline visit. * Previous liver or other organ transplantation (including engrafted bone marrow). * Any other concomitant liver disease, including hepatitis C or D. Non-alcoholic fatty liver disease (NAFLD) with steatosis &/or mild to moderate steatohepatitis is acceptable but NAFLD with severe steatohepatitis is exclusionary. * Presence of anti-hepatitis D virus (HDV) or anti-hepatitis C virus (HCV) (unless HCV RNA negative) in serum on any occasion in the 144 weeks prior to baseline visit. Presence of anti-HIV (test completed within 6 weeks prior to baseline visit). * Pre-existing psychiatric condition(s), including, but not limited to: current moderate or severe depression, history of depression requiring hospitalization within the past 10 years, history of suicidal or homicidal attempt within the past 10 years, history of severe psychiatric disorders as determined by a study physician. * History of immune-mediated or cerebrovascular disease, chronic pulmonary or cardiac disease associated with functional limitation, retinopathy, uncontrolled thyroid disease, poorly controlled diabetes or uncontrolled seizure disorder, as determined by a study physician. * Any medical condition that would, in the opinion of a study physician, be predicted to be exacerbated by therapy or that would limit study participation. * Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids or other immunosuppressive medications during the course of this study. * Evidence of active or suspected malignancy, or a history of malignancy within the 144 weeks prior to baseline visit (except adequately treated carcinoma in situ or basal cell carcinoma of the skin). * Expected need for ongoing use of any antivirals with activity against HBV during the course of the study. * Concomitant use of complementary or alternative medications purported to have antiviral activity. * Participation in any other clinical trial involving investigational drugs within 30 days of the baseline visit or intention to participate in another clinical trial involving investigational drugs during participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL | End of follow-up (up to 96 weeks) | Lack of data was considered to be treatment failure. |
| Incidence of Adverse Events (AEs) Per Person-Year of Observation | From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks) | The number of AEs includes both AEs and Serious Adverse Events (SAEs). The incidence is calculated as the number of AEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively. |
| Incidence of Serious Adverse Events (SAEs) Per Person-Year | From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks) | The incidence is calculated as the number of SAEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With HBsAg Seroconversion | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women | End of follow-up (up to 96 weeks) | — |
| Proportion of Participants With HBeAg Loss | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With HBV DNA ≤1000 IU/mL | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With HBV DNA <20 IU/mL | End of treatment (up to 48 weeks) | — |
| Absence of Detectable Antiviral Drug-resistance HBV Mutations | End of treatment (up to 48 weeks) | HBV drug resistance variant testing was performed at the CDC laboratory. The sequences of the HBV polymerase spanning nucleotide positions 311-1021 were determined by Sanger sequencing. Drug resistance mutations that were tested in this study included L80VI, L82M, T128N, W153Q, F166L, I169T, V173L, L180M, A181TV, T184ACFGILMS, V191T, A194T, A200V, S202ETV, M204IV, V207I, N236T, M250ILV, and G145R. |
| Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L) | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With HBeAg Seroconversion | End of treatment (up to 48 weeks) | — |
| Proportion of Participants With HBsAg Loss | End of treatment (up to 48 weeks) | — |
Countries
Canada, United States
Participant flow
Recruitment details
Twenty-eight (28) adults were enrolled at 11 clinical sites in the United States and Canada between 12/18/12 and 04/29/15.
Participants by arm
| Arm | Count |
|---|---|
| Peginterferon and Entecavir Entecavir 0.5 mg daily orally for 48 weeks plus peginterferon alfa-2a 180 μg subcutaneously weekly during weeks 9-48 of treatment. After treatment discontinuation, follow-up off treatment for 48 weeks. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Peginterferon and Entecavir |
|---|---|
| Age, Continuous | 37.2 years |
| Hepatitis B Virus (HBV) DNA | 8.2 log10 IU/mL |
| Race/Ethnicity, Customized Asian | 27 Participants |
| Race/Ethnicity, Customized Black/African American | 1 Participants |
| Region of Enrollment Canada | 9 Participants |
| Region of Enrollment United States | 19 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 14 / 28 |
| serious Total, serious adverse events | 1 / 28 |
Outcome results
Primary
Incidence of Adverse Events (AEs) Per Person-Year of Observation
The number of AEs includes both AEs and Serious Adverse Events (SAEs). The incidence is calculated as the number of AEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Time frame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginterferon and Entecavir | Incidence of Adverse Events (AEs) Per Person-Year of Observation | End of treatment (Up to 48 weeks) | 1.60 Events per person-year of observation |
| Peginterferon and Entecavir | Incidence of Adverse Events (AEs) Per Person-Year of Observation | End of follow-up (Up to 96) weeks | 0.86 Events per person-year of observation |
Primary
Incidence of Serious Adverse Events (SAEs) Per Person-Year
The incidence is calculated as the number of SAEs divided by the number of person-years of observation, which is the sum, across all participants, of the number of years between the start of treatment and the end of treatment, or the end of follow-up, respectively.
Time frame: From first treatment to the end of treatment (up to 48 weeks) and the end of follow-up (up to 96 weeks)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peginterferon and Entecavir | Incidence of Serious Adverse Events (SAEs) Per Person-Year | End of treatment (Up to 48 weeks) | 0 SAEs per person-year of observation |
| Peginterferon and Entecavir | Incidence of Serious Adverse Events (SAEs) Per Person-Year | End of follow-up (Up to 96 weeks) | .021 SAEs per person-year of observation |
Primary
Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL
Lack of data was considered to be treatment failure.
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBeAg Loss (Lack of Detectable HBeAg) AND HBV DNA ≤1,000 IU/mL | 0 Proportion of participants |
Secondary
Absence of Detectable Antiviral Drug-resistance HBV Mutations
HBV drug resistance variant testing was performed at the CDC laboratory. The sequences of the HBV polymerase spanning nucleotide positions 311-1021 were determined by Sanger sequencing. Drug resistance mutations that were tested in this study included L80VI, L82M, T128N, W153Q, F166L, I169T, V173L, L180M, A181TV, T184ACFGILMS, V191T, A194T, A200V, S202ETV, M204IV, V207I, N236T, M250ILV, and G145R.
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Absence of Detectable Antiviral Drug-resistance HBV Mutations | .893 Proportion of participants |
Secondary
Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With Alanine Aminotransferase (ALT) <45 U/L for Men, <30 U/L for Women | .571 Proportion of participants |
Secondary
Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With ALT <45 U/L for Men, <30 U/L for Women | .750 Proportion of participants |
Secondary
Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L) | .464 Proportion of participants |
Secondary
Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L)
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With ALT Normalization (Men <30 U/L, Women <20 U/L) | .393 Proportion of participants |
Secondary
Proportion of Participants With HBeAg Loss
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBeAg Loss | .036 Proportion of participants |
Secondary
Proportion of Participants With HBeAg Loss
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBeAg Loss | .036 Proportion of participants |
Secondary
Proportion of Participants With HBeAg Seroconversion
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBeAg Seroconversion | .036 Proportion of participants |
Secondary
Proportion of Participants With HBeAg Seroconversion
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBeAg Seroconversion | .036 Proportion of participants |
Secondary
Proportion of Participants With HBsAg Loss
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBsAg Loss | 0 Proportion of participants |
Secondary
Proportion of Participants With HBsAg Loss
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBsAg Loss | 0 Proportion of participants |
Secondary
Proportion of Participants With HBsAg Seroconversion
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBsAg Seroconversion | 0 Proportion of participants |
Secondary
Proportion of Participants With HBsAg Seroconversion
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBsAg Seroconversion | 0 Proportion of participants |
Secondary
Proportion of Participants With HBV DNA ≤1000 IU/mL
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBV DNA ≤1000 IU/mL | 0 Proportion of participants |
Secondary
Proportion of Participants With HBV DNA ≤1000 IU/mL
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBV DNA ≤1000 IU/mL | .929 Proportion of participants |
Secondary
Proportion of Participants With HBV DNA <20 IU/mL
Time frame: End of treatment (up to 48 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBV DNA <20 IU/mL | .179 Proportion of participants |
Secondary
Proportion of Participants With HBV DNA <20 IU/mL
Time frame: End of follow-up (up to 96 weeks)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peginterferon and Entecavir | Proportion of Participants With HBV DNA <20 IU/mL | 0 Proportion of participants |