| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| genotype 1 chronic hepatitis C infection of high viral titer and baseline body weight greater than or equal to 85 kg |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the efficacy and safety of 360 µg induction dosing of Pegasys for 12 weeks followed by a 180 µg maintenance dose of Pegasys for 36 weeks in combination with Copegus for 48 weeks with the efficacy and safety of 180 µg fixed dosing of Pegasys in combination with Copegus for 48 weeks in patients with genotype 1 chronic hepatitis C infection of high viral titer and baseline body weight equal to or greater than 85 kg |
|
| E.2.2 | Secondary objectives of the trial |
| Compare efficacy and safety of higher dose Copegus (Cop) in combination with Pegasys (Peg) for 48 wks with efficacy and safety of standard dose Cop in combination with Peg for 48 wks. Compare efficacy and safety of 360 µg induction dosing of Peg for 12 wks followed by a 180 µg maintenance dose of Peg for 36 wks in combination with higher dose Cop with efficacy and safety of the approved Peg plus Cop dosing regimen. Determine if treatment-related lymphopenia and neutropenia are associated with the occurrence of serious infections. Evaluate Peg and ribavirin drug exposures and their relationship to viral response in a subset treated with 360 µg induction dosing of Peg and with higher doses of Cop within the four study groups. Evaluate effect of combination of Peg and Cop on gene expression in responders and nonresponders to treatment. Evaluate association between mutations of the NS5A and NS5B genes of HCV and virological response in a subset of responders and nonresponders. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible for this trial, patients must have documentation of the following:
• Age >=18 years
• Body weight >= 85 kg
• Serologic evidence of CHC infection by an anti-HCV antibody test (current or historical)
• Evidence of hepatitis C genotype 1 infection by molecular assay
• Serum HCV RNA quantifiable at >= 400,000 IU/mL by the Roche TaqMan HCV Test
• Chronic liver disease consistent with CHC infection on a biopsy obtained within the past 24 calendar months as judged by a central pathologist. For patients with incomplete/transition to cirrhosis or cirrhosis, a biopsy within 36 calendar months before the first dose is sufficient. A maximum of 20% of patients with cirrhosis or incomplete/transition to cirrhosis will be permitted to enroll in the trial.
• Patients with cirrhosis or incomplete/transition to cirrhosis must have an abdominal ultrasound, computerized tomographic (CT) scan, or magnetic resonance imaging (MRI) scan without evidence of hepatocellular carcinoma (within 2 months prior to randomization) and a serum alpha-fetoprotein (AFP) <100 ng/mL
• Compensated liver disease (Child-Pugh Grade A clinical classification only)
• Negative urine pregnancy test result (for females of childbearing potential) documented within the 24-hour period prior to the first dose of study drugs. Additionally, all female patients of childbearing potential and all males with female partners of childbearing potential must use two forms of effective contraception (combined) during treatment and 6 months after treatment end
• Willingness to give written informed consent and willingness to participate in and comply with the study requiremen |
|
| E.4 | Principal exclusion criteria |
Patients with any of the following will not be eligible for participation:
• Infection with HCV genotype 1 mixed with a genotype other than genotype 2 or genotype 3 or infection with an indeterminate genotype. Patients with indeterminate or mixed genotype 1 subtypes will be allowed.
• History of having received interferon alpha (IFN), PEG-IFN, ribavirin, viramidine, levovirin, or investigational HCV protease or polymerase inhibitors at any previous time, or any other systemic antiviral therapy with established or perceived activity against the hepatitis C virus =<3 months prior to the first dose of study drug
• History of having received any investigational drug =< 3 months prior to the first dose of study drug or the expectation that such drugs will be used during the study. Patients enrolled in this study cannot be enrolled in another study for either research, diagnostic or treatment purposes.
• Patients who are expected to need systemic antiviral therapy with established or perceived activity against HCV at any time during their participation in the study are also excluded
• Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or anti-HIV Ab • History or other evidence of a medical condition associated with chronic liver disease other than CHC (eg, hemochromatosis, autoimmune hepatitis, metabolic liver disease, alcoholic liver disease, toxin exposures) • Females who are pregnant or breast-feeding
• Male partners of females who are pregnant
• Absolute neutrophil count (ANC) <1500 cells/mm3
• Platelet count <90,000 cells/mm3
• Hemoglobin concentration <12 g/dL in females or <13 g/dL in males or any patient with a baseline increased risk for anemia (eg, thalassemia, sickle cell anemia, spherocytosis, history of gastrointestinal bleeding) or for whom anemia would be medically problematic
• Serum creatinine concentration >1.5 times the upper limit of normal at screening
• The use of colony stimulating factors such as granulocyte colony stimulating factor (G-CSF), erythropoetin or other therapeutic agents to elevate hematology arameters to facilitate patient entry into the study
• History of severe psychiatric disease, including psychosis and/or depression, characterized by a suicide attempt, hospitalization for psychiatric disease, or a period of disability as a result of psychiatric disease
• Beck Depression Inventory (BDI) score of >= 20
• History of immunologically mediated disease (eg, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis (defined as affecting >10% of the body, here the palm of one hand equals 1%, or if the hands and feet are affected), rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory medications for management
• History or other evidence of decompensated liver disease or a Child-Pugh score >6. Coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices are conditions consistent with decompensated liver disease
• History or other evidence of chronic pulmonary disease associated with functional limitation
• History of severe cardiac disease (eg, NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular diseases). In addition, patients with documented or presumed coronary artery disease or cerebrovascular disease should not be enrolled if, in the judgment of the investigator, an acute decrease in hemoglobin by up to 4 g/dL (as may be seen with ribavirin therapy) would not be well-tolerated
• History of uncontrolled severe seizure disorder
• Evidence of an active or suspected cancer or a history of malignancy within the last 2 years. Patients with a lesion suspicious for hepatic malignancy on the screening imaging study will be eligible only if the likelihood of carcinoma is =< 10% following an appropriate evaluation
• History of any systemic antineoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids or radiation) =<6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study
• Poorly controlled thyroid dysfunction
• History or other evidence of a clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension or history or other evidence of severe retinopathy (eg, cytomegalovirus retinitis, macular degeneration)
• History of major organ transplantation with an existing functional graft
• History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
• Evidence of alcohol, drug, or substance abuse within 1 year of first dose |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary measure of efficacy will be SVR defined as the percentage of patients with undetectable HCV RNA as measured by the Roche TaqMan HCV Test (detection limit = 15 IU/mL) at 24 weeks after completion of the treatment period (a single last HCV RNA PCR <15 IU/mL measured ≥ week 68 (ie, ≥ study day 477)). Patients without measurements at the end of the 24-week untreated follow-up period will be considered as non-responders. This endpoint will be labeled as “the SVR-24 according to the scheduled treatment period”. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| the last observation of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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