Hepatitis B, Chronic
Conditions
Brief summary
This study is being done to compare the safety and efficacy of PEG-Intron™ to that of PEGASYS™ in participants with chronic hepatitis B (hepatitis B envelope antigen \[HBeAg\] positive or negative) who have not previously been treated with interferon.
Interventions
BIOLOGICALPEG-Intron™
PEG-Intron subcutaneously (SC) once weekly for a total of 48 weeks
BIOLOGICALPEGASYS™
PEGASYS subcutaneously (SC) once weekly for a total of 48 weeks
Sponsors
Merck Sharp & Dohme LLC
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
* Must be able to adhere to dose and visit schedules * ≥ 40 kg * Hepatitis B surface antigen (HBsAg) positive for at least 6 months * Anti-HBs negative * Female participants of childbearing potential must agree to use an acceptable method of contraception from at least 2 weeks prior to Day 1 and continue until at least 1 month after last dose of study drug Inclusion Criteria for HBeAg(+) participants: * HBeAg(+) * Anti-HBe(-) Inclusion Criteria for HBeAg(-) participants: * HBeAg(-) * Anti-HBe(+)
Exclusion criteria
* Co-infection with the human immunodeficiency virus (HIV) or hepatitis C or hepatitis D virus * Prior treatment with interferon for hepatitis B * Use of nucleoside/nucleotide analogues within 6 months of the screening visit or at any time during the study * Use of any investigational drug within 30 days of the screening visit * Prior treatment with herbal remedies with known hepatotoxicity. All herbal remedies used for hepatitis B treatment must be discontinued before Day 1 * Evidence of decompensated liver disease including, but not limited to, a history or presence of clinical ascites, bleeding varices, or hepatic encephalopathy * Diabetic and/or hypertensive with clinically significant ocular examination findings * History of stroke or transient ischemic attack * Immunologically mediated disease (e.g., inflammatory bowel disease \[Crohn's disease, ulcerative colitis\], celiac disease, rheumatoid arthritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, sarcoidosis, severe psoriasis requiring oral or injected treatment, or symptomatic thyroid disorder) * Chronic pulmonary disease (e.g., chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sarcoidosis) * Current or history of any clinically significant cardiac abnormalities/dysfunction * Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial * Myelodysplastic syndromes * Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair * Pregnant or nursing, or intending to become pregnant during the trial period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of HBeAg(+) Participants Achieving HBeAg Seroconversion at 24 Weeks Post-treatment | FU Week 24 (Study Week 72) | Blood samples were drawn to assess the participant's seroconversion status at Follow-up (FU) Week 24. HBeAg seroconversion was defined as loss of HBeAg in HBeAg(+) participants and development of antibody to HBeAg. |
| Percentage of HBeAg(-) Participants Achieving Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels <2000 IU/mL at 24 Weeks Post-treatment | FU Week 24 (Study Week 72) | The Roche COBAS TaqMan HBV-(High Pure System Assay) was used to measure HBV DNA in blood samples of HBeAg(-) participants. The percentage of HBeAg(-) participants with HBV DNA \<2000 IU/mL at 24 weeks post-treatment was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of HBeAg(+) Participants Achieving HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | FU Week 24 (Study Week 72) | The Roche COBAS TaqMan HBV-(High Pure System Assay) was used to measure HBV DNA in blood samples of HBeAg(+)participants. The percentage of HBeAg(+) participants with HBV DNA \<2000 IU/mL at 24 weeks post-treatment was reported. |
| Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment | FU Week 24 (Study Week 72) | ALT normalization is a desired goal of HBV treatment, which is defined as having abnormal ALT levels at baseline and subsequently normal ALT levels after receiving treatment, where normal is defined as ≤ 1x the upper limit of normal (ULN). The percentage of HBeAg(+) and HBeAg(-) participants achieving ALT normalization at 24 weeks post-treatment was reported. |
| Percentage of HBeAg(+) Participants Achieving the Combined Response of HBeAg Seroconversion and HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | FU Week 24 (Study Week 72) | HBeAg seroconversion was defined as loss of HBeAg in HBeAg(+) participants and development of antibody to HBeAg. HBV DNA levels in blood were measured by the Roche COBAS TaqMan HBV-(High Pure System Assay). The percentage of HBeAg(+) participants with the combined response of achieving both HBeAg conversion and HBV DNA levels \<2000 IU/mL at 24 weeks post-treatment was reported. |
Participant flow
Recruitment details
Hepatitis B envelope antigen (HBeAg)-positive or -negative participants who were interferon treatment-naïve were recruited from 81 sites to be randomly assigned to receive pegylated inferferon alfa-2b (PEG-Intron™) or pegylated interferon alfa-2a (PEGASYS™).
Pre-assignment details
402 participants were enrolled and 399 participants were treated on study.
Participants by arm
| Arm | Count |
|---|---|
| HBeAg(+) PEG-Intron HBeAg-positive participants receive 1.5 mcg/kg/wk PEG-Intron subcutaneously (SC) once weekly for 48 weeks. | 142 |
| HBeAg(+) PEGASYS HBeAg-positive participants receive 180 mcg/kg/wk PEGASYS SC once weekly for 48 weeks. | 144 |
| HBeAg(-) PEG-Intron HBeAg-negative participants receive 1.5 mcg/kg/wk PEG-Intron SC once weekly for 48 weeks. | 56 |
| HBeAg(-) PEGASYS HBeAg-negative participants receive 180 mcg/kg/wk PEGASYS SC once weekly for 48 weeks. | 57 |
| Total | 399 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 2 | 3 | 1 |
| Overall Study | Lost to Follow-up | 2 | 2 | 1 | 0 |
| Overall Study | Not Treated | 1 | 1 | 1 | 0 |
| Overall Study | Physician Decision | 6 | 5 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 5 | 6 | 1 |
Baseline characteristics
| Characteristic | HBeAg(+) PEG-Intron | HBeAg(+) PEGASYS | HBeAg(-) PEG-Intron | HBeAg(-) PEGASYS | Total |
|---|---|---|---|---|---|
| Age, Continuous | 32.6 years STANDARD_DEVIATION 7.73 | 33.6 years STANDARD_DEVIATION 9.23 | 41.1 years STANDARD_DEVIATION 10.77 | 42.0 years STANDARD_DEVIATION 10.5 | 35.5 years STANDARD_DEVIATION 9.91 |
| Race/Ethnicity, Customized Asian | 142 participants | 144 participants | 56 participants | 57 participants | 399 participants |
| Sex: Female, Male Female | 54 Participants | 43 Participants | 21 Participants | 15 Participants | 133 Participants |
| Sex: Female, Male Male | 88 Participants | 101 Participants | 35 Participants | 42 Participants | 266 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 | 126 / 142 | 124 / 144 | 50 / 56 | 50 / 57 |
| serious Total, serious adverse events | 12 / 142 | 10 / 144 | 1 / 56 | 2 / 57 |
Outcome results
Primary
Percentage of HBeAg(+) Participants Achieving HBeAg Seroconversion at 24 Weeks Post-treatment
Blood samples were drawn to assess the participant's seroconversion status at Follow-up (FU) Week 24. HBeAg seroconversion was defined as loss of HBeAg in HBeAg(+) participants and development of antibody to HBeAg.
Time frame: FU Week 24 (Study Week 72)
Population: All randomized HBeAg(+) participants who received ≥1 dose of study medication. HBeAg(-) participants were not analyzed for HBeAg seroconversion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg(+) PEG-Intron | Percentage of HBeAg(+) Participants Achieving HBeAg Seroconversion at 24 Weeks Post-treatment | 25.4 percentage of participants |
| HBeAg(+) PEGASYS | Percentage of HBeAg(+) Participants Achieving HBeAg Seroconversion at 24 Weeks Post-treatment | 23.6 percentage of participants |
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (hepatitis B Virus \[HBV\] genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-8.4, 11.6]
Primary
Percentage of HBeAg(-) Participants Achieving Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels <2000 IU/mL at 24 Weeks Post-treatment
The Roche COBAS TaqMan HBV-(High Pure System Assay) was used to measure HBV DNA in blood samples of HBeAg(-) participants. The percentage of HBeAg(-) participants with HBV DNA \<2000 IU/mL at 24 weeks post-treatment was reported.
Time frame: FU Week 24 (Study Week 72)
Population: All randomized HBeAg(-) participants who received ≥1 dose of study medication. HBeAg(+) participants were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg(-) PEG-Intron | Percentage of HBeAg(-) Participants Achieving Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels <2000 IU/mL at 24 Weeks Post-treatment | 30.4 percentage of participants |
| HBeAg(-) PEGASYS | Percentage of HBeAg(-) Participants Achieving Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels <2000 IU/mL at 24 Weeks Post-treatment | 33.3 percentage of participants |
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (HBV genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-20.2, 14.3]
Secondary
Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment
ALT normalization is a desired goal of HBV treatment, which is defined as having abnormal ALT levels at baseline and subsequently normal ALT levels after receiving treatment, where normal is defined as ≤ 1x the upper limit of normal (ULN). The percentage of HBeAg(+) and HBeAg(-) participants achieving ALT normalization at 24 weeks post-treatment was reported.
Time frame: FU Week 24 (Study Week 72)
Population: All randomized HBeAg(+) and HBeAg(-) participants who received ≥1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg(+) PEG-Intron | Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment | 49.3 percentage of participants |
| HBeAg(+) PEGASYS | Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment | 47.2 percentage of participants |
| HBeAg(-) PEG-Intron | Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment | 71.4 percentage of participants |
| HBeAg(-) PEGASYS | Percentage of HBeAg(+) and HBeAg(-) Participants Achieving Alanine Aminotransferase (ALT) Normalization at 24 Weeks Post-treatment | 61.4 percentage of participants |
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (HBV genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-9.5, 13.6]
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (HBV genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-7.2, 27.1]
Secondary
Percentage of HBeAg(+) Participants Achieving HBV DNA <2000 IU/mL at 24 Weeks Post-treatment
The Roche COBAS TaqMan HBV-(High Pure System Assay) was used to measure HBV DNA in blood samples of HBeAg(+)participants. The percentage of HBeAg(+) participants with HBV DNA \<2000 IU/mL at 24 weeks post-treatment was reported.
Time frame: FU Week 24 (Study Week 72)
Population: All randomized HBeAg(+) participants who received ≥1 dose of study medication. HBeAg(-) participants were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg(+) PEG-Intron | Percentage of HBeAg(+) Participants Achieving HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | 23.9 percentage of participants |
| HBeAg(+) PEGASYS | Percentage of HBeAg(+) Participants Achieving HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | 21.5 percentage of participants |
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (HBV genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-7.2, 12.3]
Secondary
Percentage of HBeAg(+) Participants Achieving the Combined Response of HBeAg Seroconversion and HBV DNA <2000 IU/mL at 24 Weeks Post-treatment
HBeAg seroconversion was defined as loss of HBeAg in HBeAg(+) participants and development of antibody to HBeAg. HBV DNA levels in blood were measured by the Roche COBAS TaqMan HBV-(High Pure System Assay). The percentage of HBeAg(+) participants with the combined response of achieving both HBeAg conversion and HBV DNA levels \<2000 IU/mL at 24 weeks post-treatment was reported.
Time frame: FU Week 24 (Study Week 72)
Population: All randomized HBeAg(+) participants who received ≥1 dose of study medication. HBeAg(-) participants were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HBeAg(+) PEG-Intron | Percentage of HBeAg(+) Participants Achieving the Combined Response of HBeAg Seroconversion and HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | 14.8 percentage of participants |
| HBeAg(+) PEGASYS | Percentage of HBeAg(+) Participants Achieving the Combined Response of HBeAg Seroconversion and HBV DNA <2000 IU/mL at 24 Weeks Post-treatment | 13.9 percentage of participants |
Comparison: The treatment difference in the rates (PEG-Intron arm minus PEGASYS™ arm) and its 95% confidence interval adjusted for the baseline stratification factor (HBV genotype) was computed using the method of Miettinen and Nurminen weighted by stratum sample size.95% CI: [-7.4, 9.2]