Hepatitis C, Chronic
Conditions
Brief summary
The objective is to compare the safety and efficacy of the following three treatment regimens in previously untreated adult subjects with chronic hepatitis C infected with Genotype 1: (1) PegIntron 1.5 µg/kg/wk in combination with weight based REBETOL (800-1400 mg/day); (2) PegIntron 1µg/kg/wk in combination with weight based REBETOL (800-1400 mg/day); and (3) PEGASYS 180 µg/wk plus COPEGUS 1000-1200 mg/day.
Detailed description
PegIntron Dose will be administered once weekly subcutaneously on the same day of the week: Screening 2 Weight 40-50 kg Volume to Inject (mL) 0.22; Screening 2 Weight 51-60 kg Volume to Inject (mL) 0.28; Screening 2 Weight 61-75 kg Volume to Inject (mL) 0.33; Screening 2 Weight 76-85 kg Volume to Inject (mL) 0.41; Screening 2 Weight 86-104 kg Volume to Inject (mL) 0.48; Screening 2 Weight 105-125 kg Volume to Inject (mL) 0.58 from two vials REBETOL Dosage (for Use With PegIntron): Screening 2 Weight 40-65 kg Daily Dose 800 mg; Screening 2 Weight \>65-85 kg Daily Dose 1000 mg; Screening 2 Weight \>85-105 kg Daily Dose 1200 mg; Screening 2 Weight \>105-125 kg Daily Dose 1400 mg The PEGASYS dose of 1 mL (180 µg) will be administered once weekly subcutaneously on the same day of the week COPEGUS Dosage (for Use With PEGASYS): Screening 2 Weight \<75 kg Daily Dose 1000 mg; Screening 2 Weight \> or = 75 kg Daily Dose 1200mg NOTE: Double Blind for PegIntron; Open Label for REBETOL, PEGASYS and COPEGUS NOTE: REBETOL is the Schering-Plough brand name for ribavirin. COPEGUS is the Hoffman-La Roche brand name for ribavirin.
Interventions
1.5 ug/kg/week subcutaneously (SC) for 48 weeks
weight based dose 800-1400 mg/day orally (PO) for 48 weeks
BIOLOGICALPEGASYS (peginterferon alfa-2a)
180 ug/week SC administered for 48 weeks
1000-1200 mg/day PO for 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 70 Years
Healthy volunteers
No
Inclusion criteria
* Previously untreated adults with chronic hepatitis C (hepatitis C virus ribonucleic acid \[HCV RNA\] quantitative polymerase chain reaction \[qPCR\] plasma positive) * Individuals with HCV genotype 1 (mixed 1a/1b is acceptable) * Compensated liver disease * Pretreatment liver biopsy slides available * Adults aged 18-70 * Individuals weighing 88-275 pounds (40-125 kg) * Free from substance abuse for past 2 years * Those suffering from diabetes and/or hypertension must have normal eye exams and retinal photographs (these will be done as part of the study before hepatitis C treatment is given) * Patients and partners of patients willing to use adequate contraception during the course of the study * Hematology laboratory results of: * Hemoglobin (HGB) ≥ 12 g/dL for females or ≥ 13g/dL for males * White Blood Cell Count (WBC) ≥ 3,000/mm\^3 * Neutrophils ≥ 1,500/mm\^3 * Platelets ≥ 80,000/mm\^3 * Chemistry laboratory results of: * Normal Thyroid Stimulating Hormone (TSH), albumin, creatinine, and direct bilirubin * Antinuclear antibody (ANA) ≤ 1:320 * Fasting Glucose 70-140 mg/dL Note: If glucose levels are between 116-140 mg/dL or an individual has diabetes, glycosylated hemoglobin \[HbA1C\] must be ≤ 8.5%
Exclusion criteria
* Previous hepatitis C treatment * Pregnant women or partners of pregnant women * Patients or partners of patients who intend to become pregnant any time during the 48 weeks * Women who are breastfeeding * Individuals with liver disease not caused by hepatitis C * Individuals infected with the hepatitis B virus and/or human immunodeficiency virus (HIV) * Patients with a history of liver cancer (hepatocellular carcinoma) * Known blood disorders such as hemoglobinopathy, coagulopathy, or glucose-6-phosphate dehydrogenase \[G6PD\] deficiency * Body organ transplant * Any known or suspected cancer within the past 5 years * Individuals who currently use epoetin \[EPO\], granulocyte colony stimulating factor \[G-CSF\] and/or granulocyte monocyte colony stimulating factor \[GM-CSF\] * Those having a history of or active clinical gout * Individuals who have chronic pulmonary disease * Individuals who have a medical condition that would likely require systemic steroids * Those with a history of central nervous system (CNS trauma) or seizure disorders * Current or previous use of lithium or antipsychotic drugs * Individuals who currently have or show signs of moderate to severe depression or history of significant psychiatric disorders * Patients with clinically significant electrocardiogram (ECG) abnormalities * Individuals with serious heart problems such as those who have had a heart attack, uncontrolled high blood pressure, or other heart problems * Patients that weigh \> 231-275 pounds (105-125 kg) AND have a body mass index (BMI) \> 30 AND have 3 or more of the risk factors below: (a) Strong family history of coronary heart disease (CHD) which includes 2 or more first-degree relatives with CHD or family history of early CHD at age \< 55 for male relatives or \< 65 for female relatives (b) Individuals with abnormal total cholesterol and/or sub fractions (uncontrolled hypercholesterolemia) (c) Diabetes (d) Hypertension (e) Smoking
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sustained Virologic Response (SVR) Rate | Assessed at the end of a 24-week post-treatment follow-up | SVR rate is the percentage of participants with undetectable hepatitis C virus ribonucleic acid (HCV-RNA) at the end of the 24-week post-treatment follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Log Viral Load at Treatment Week 4 | Assessed at Baseline and Treatment Week 4 | The difference between viral load levels in the blood at the start of the study and Treatment Week 4, expressed in terms of a logarithmic scale with base 10, and averaged for all the participants in each treatment group. |
| Virologic Response Rate at Treatment Week 12 | Assessed at Treatment Week 12 | Percentage of participants with undetectable hepatitis C RNA (HCV-RNA) at Treatment Week 12 |
| Mean Change From Baseline in the Log Viral Load at Treatment Week 2 | Assessed at Baseline and Treatment Week 2 | The difference between viral load levels in the blood at the start of the study and Treatment Week 2, expressed in terms of a logarithmic scale with base 10, and averaged for all the participants in each treatment group. |
Participant flow
Pre-assignment details
Enrolled 4469 subjects; Randomized 3083; Treated 3070
Participants by arm
| Arm | Count |
|---|---|
| PegIntron 1.5 ug/kg/wk Plus REBETOL PegIntron (peginterferon alfa-2b; SCH 54031) 1.5 ug/kg/week in combination with weight-based REBETOL (ribavirin; SCH 18908) 800-1400 mg/day administered for 48 weeks with 24-week post-treatment follow-up | 1,019 |
| PegIntron 1.0 ug/kg/wk Plus REBETOL PegIntron (peginterferon alfa-2b; SCH 54031) 1.0 ug/kg/week in combination with weight-based REBETOL (ribavirin; SCH 18908) 800-1400 mg/day administered for 48 weeks with 24-week post-treatment follow-up | 1,016 |
| PEGASYS 180 ug/wk Plus COPEGUS PEGASYS (peginterferon alfa-2a) 180 ug/week plus COPEGUS (ribavirin) 1000-1200 mg/day administered for 48 weeks with 24-week post-treatment follow-up | 1,035 |
| Total | 3,070 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative | 1 | 0 | 1 |
| Overall Study | Adverse Event | 130 | 98 | 136 |
| Overall Study | Did not meet protocol eligibility | 2 | 0 | 3 |
| Overall Study | Lack of Efficacy | 262 | 357 | 211 |
| Overall Study | Lost to Follow-up | 45 | 34 | 45 |
| Overall Study | Other | 2 | 7 | 8 |
| Overall Study | Protocol Violation | 15 | 10 | 10 |
| Overall Study | Withdrawal by Subject | 45 | 40 | 42 |
Baseline characteristics
| Characteristic | PegIntron 1.5 ug/kg/wk Plus REBETOL | PegIntron 1.0 ug/kg/wk Plus REBETOL | PEGASYS 180 ug/wk Plus COPEGUS | Total |
|---|---|---|---|---|
| Age, Continuous | 47.5 years STANDARD_DEVIATION 7.8 | 47.5 years STANDARD_DEVIATION 8.1 | 47.6 years STANDARD_DEVIATION 8.2 | 47.5 years STANDARD_DEVIATION 8 |
| Sex: Female, Male Female | 406 Participants | 409 Participants | 422 Participants | 1237 Participants |
| Sex: Female, Male Male | 613 Participants | 607 Participants | 613 Participants | 1833 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 | 996 / 1,019 | 1,000 / 1,016 | 1,018 / 1,035 |
| serious Total, serious adverse events | 88 / 1,019 | 94 / 1,016 | 121 / 1,035 |
Outcome results
Primary
Sustained Virologic Response (SVR) Rate
SVR rate is the percentage of participants with undetectable hepatitis C virus ribonucleic acid (HCV-RNA) at the end of the 24-week post-treatment follow-up.
Time frame: Assessed at the end of a 24-week post-treatment follow-up
Population: Intent-to-Treat \[ITT\] Population defined as subjects who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PegIntron 1.5 ug/kg/wk Plus REBETOL | Sustained Virologic Response (SVR) Rate | 39.8 Percentage of participants |
| PegIntron 1.0 ug/kg/wk Plus REBETOL | Sustained Virologic Response (SVR) Rate | 38.0 Percentage of participants |
| PEGASYS 180 ug/wk Plus COPEGUS | Sustained Virologic Response (SVR) Rate | 40.9 Percentage of participants |
p-value: 0.56795% CI: [0.79, 1.14]Regression, Logistic
p-value: 0.19595% CI: [0.9, 1.3]Regression, Logistic
Secondary
Mean Change From Baseline in the Log Viral Load at Treatment Week 2
The difference between viral load levels in the blood at the start of the study and Treatment Week 2, expressed in terms of a logarithmic scale with base 10, and averaged for all the participants in each treatment group.
Time frame: Assessed at Baseline and Treatment Week 2
Population: ITT Population defined as subjects who received at least one dose of study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PegIntron 1.5 ug/kg/wk Plus REBETOL | Mean Change From Baseline in the Log Viral Load at Treatment Week 2 | -1.55 Log10 IU/mL | Standard Deviation 1.2 |
| PegIntron 1.0 ug/kg/wk Plus REBETOL | Mean Change From Baseline in the Log Viral Load at Treatment Week 2 | -1.30 Log10 IU/mL | Standard Deviation 1.12 |
| PEGASYS 180 ug/wk Plus COPEGUS | Mean Change From Baseline in the Log Viral Load at Treatment Week 2 | -1.60 Log10 IU/mL | Standard Deviation 1.24 |
Secondary
Mean Change From Baseline in the Log Viral Load at Treatment Week 4
The difference between viral load levels in the blood at the start of the study and Treatment Week 4, expressed in terms of a logarithmic scale with base 10, and averaged for all the participants in each treatment group.
Time frame: Assessed at Baseline and Treatment Week 4
Population: ITT Population defined as subjects who received at least one dose of study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PegIntron 1.5 ug/kg/wk Plus REBETOL | Mean Change From Baseline in the Log Viral Load at Treatment Week 4 | -2.32 Log10 IU/mL | Standard Deviation 1.5 |
| PegIntron 1.0 ug/kg/wk Plus REBETOL | Mean Change From Baseline in the Log Viral Load at Treatment Week 4 | -2.02 Log10 IU/mL | Standard Deviation 1.42 |
| PEGASYS 180 ug/wk Plus COPEGUS | Mean Change From Baseline in the Log Viral Load at Treatment Week 4 | -2.45 Log10 IU/mL | Standard Deviation 1.52 |
Secondary
Virologic Response Rate at Treatment Week 12
Percentage of participants with undetectable hepatitis C RNA (HCV-RNA) at Treatment Week 12
Time frame: Assessed at Treatment Week 12
Population: ITT Population defined as subjects who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PegIntron 1.5 ug/kg/wk Plus REBETOL | Virologic Response Rate at Treatment Week 12 | 39.9 Percentage of participants |
| PegIntron 1.0 ug/kg/wk Plus REBETOL | Virologic Response Rate at Treatment Week 12 | 36.0 Percentage of participants |
| PEGASYS 180 ug/wk Plus COPEGUS | Virologic Response Rate at Treatment Week 12 | 45.0 Percentage of participants |
95% CI: [36.9, 42.9]
95% CI: [33.1, 39]
95% CI: [42, 48.1]