| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C (CHC), Genotype 1 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Genotype 1 Chronic Hepatitis C patients who have had a prior null response to treatment with peginterferon plus ribavirin |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| 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 estimate the sustained virologic response 12 weeks after treatment (SVR-12) for each of the following three experimental treatment groups (regimens containing RO5024048, telaprevir, Pegasys®, and Copegus®) in patients with previous null response to PEG-IFN/RBV combination therapy, defined as a < 2 log10 IU/mL decrease in viral titer after at least 12 weeks of treatment with PEG-IFN/RBV
- RO5024048 in combination with telaprevir and Pegasys/Copegus administered for 12 weeks followed by RO5024048 and Pegasys/Copegus administered for 12 weeks
- RO5024048 in combination with telaprevir and Pegasys/Copegus administered for 12 weeks followed by RO5024048 and Pegasys/Copegus administered for 12 weeks followed by Pegasys/Copegus administered for 24 weeks
- RO5024048 in combination with telaprevir and Pegasys/Copegus administered for 12 weeks followed by RO5024048/placebo and Pegasys/Copegus administered for 12 weeks, followed by Pegasys/Copegus administered for 24 weeks |
|
| E.2.2 | Secondary objectives of the trial |
• To estimate the sustained virologic response 4 weeks after treatment (SVR-4) for each of the three experimental treatment groups
• To estimate the sustained virologic response 24 weeks after treatment (SVR-24) for each of the three experimental treatment groups
• To estimate the virologic response over time (all visits) for each of the three experimental treatment groups
• To estimate the proportion of patients who develop resistance to telaprevir and/or RO5024048 in each of the three experimental treatment groups
• To compare the safety and tolerability of the treatment groups |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or female aged 18 years and older
• Serologic evidence of CHC infection by an anti-HCV antibody (Ab) test (current or historical)
• Evidence of CHC infection > 6 months duration
• Serum HCV RNA quantifiable at ≥ 50,000 IU/mL as demonstrated by the Roche COBAS® TaqMan® HCV Test
• Evidence of HCV genotype 1a or 1b infection by molecular assay
• The following information related to the patient’s response to the previous course of PEG-IFN/RBV therapy must be available in the medical records of the patient: (1) approved doses of prior PEG-IFN/RBV treatment and the start/end date of previous treatment with PEG-IFN/RBV, (2) documentation of previous dose modifications or interruptions (or lack thereof) to ensure documentation of previous compliance with therapy, (3) HCV RNA prior to the start of previous treatment and at 12 weeks after the start of treatment (window of Week 11 to Week 16) showing a null response, defined as a < 2 log10 IU/mL decrease in viral titer after at least 12 weeks of treatment with PEG-IFN/RBV, (4) HCV assay used, and (5) limit of detection of the assay used.
• Chronic liver disease consistent with CHC infection as seen via biopsy, using the scoring methods in Appendix B . Patients designated as not having cirrhosis or incomplete/transition to cirrhosis must have had a liver biopsy consistent with CHC within 24 calendar months of the first dose. For patients with cirrhosis or incomplete/transition to cirrhosis, there is no time frame for the biopsy. Fibroscan assessment is allowed in such patients but must be performed within 12 calendar months of the first dose. An elasticity score of ≥ 12.5 kPa will be used to designate incomplete/transition to cirrhosis or cirrhosis (i.e., ‘cirrhotic’). If an elasticity score of ≥ 9.5 kPa but < 12.5 kPa is returned the patient must receive a liver biopsy to determine whether his or her case is described as ‘cirrhotic’ or ‘non-cirrhotic’. |
|
| E.4 | Principal exclusion criteria |
• Positive test at screening for anti–hepatitis A virus (HAV) IgM Ab, hepatitis B surface antigen (HBsAg), or anti-HIV Ab
• History of having received RO5024048/telaprevir or any cross-resistant DAA agent at any previous time or use of any other systemic antiviral therapy with established or perceived activity against HCV ≤ 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.
• History or other evidence of a medical condition associated with chronic liver disease other than HCV (e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, alpha-1 antitrypsin deficiency, alcoholic liver disease, and/or toxin exposure)
• Females who are pregnant or breastfeeding
• Males with female partners who are pregnant
• Absolute neutrophil count (ANC) < 1.5 × 103 cells/μL (< 1.5 × 109 cells/L)
• Platelet count < 90 × 103 cells/μL (< 90 × 109 cells/L)
• Hemoglobin concentration < 12 g/dL (120 g/L) in females or < 13 g/dL (130 g/L) in males or a baseline increased risk for anemia (e.g., thalassemia, sickle cell anemia, spherocytosis, history of gastrointestinal bleeding) or in those for whom anemia would be medically problematic
• The use of colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), erythropoietin, blood transfusion, or other therapeutic agents to elevate hematology parameters to facilitate patient entry into the study within the last 6 months
• Any patient with a 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 who does not agree to have a psychiatric evaluation at screening and who does not agree to have continued monitoring by a mental health specialist at least every 4 weeks during the study
• History of immunologically mediated disease (e.g., vasculitis, cryoglobulinemia, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid arthritis requiring more than intermittent non-steroidal anti-inflammatory medications for management).
• History or other evidence of decompensated liver disease. Coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices are conditions consistent with decompensated liver disease.
• Serum creatinine > 1.5 times the ULN
• History of pre-existing renal disease. Patients with a history of nephrolithiasis will be allowed.
• Estimated creatinine clearance (CRCL) of ≤ 70 mL/min (≤ 1.17 mL/sec), calculated by the Cockcroft-Gault formula (see Appendix C)
• Type 1 or 2 diabetes with glycosylated hemoglobin (HbA1c) of ≥ 8.5% at the screening visit
• History or other evidence of chronic pulmonary disease associated with functional limitation
• History of severe cardiac disease (e.g., New York Heart Association Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmia requiring ongoing treatment, unstable angina, or other significant cardiovascular disease). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Sustained virologic response (SVR-12) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• To estimate SVR-4 for each experimental treatment group
• To estimate the virologic response over time (all visits) for each experimental group
• To estimate the proportion of patients who develop resistance to telaprevir and/or RO5024048 in each of the three experimental treatment groups
• To compare the safety and tolerability of the treatment groups |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Baseline and all post-baseline visits |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Drug-Resistance, Samples for Roche Clinical Repository |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 | No |
| 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 |
| Canada |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| 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 end of the study is defined as the date when the last patient last visit (LPLV) occurs. Last patient last visit is defined as either the date of the last patient visit of the last patient to complete the study or the date at which the last data point from the last patient—which was required for statistical analysis (i.e., key safety and efficacy results for decision-making)—was received, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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