| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Genotype 1 Virus Infection (Treatment-Naïve Patients) |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| 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 evaluate the safety, tolerability, and effect on virologicalresponse of a 12 and 24-week duration of RO5190591 incombination with Pegasys and Copegus compared to thecombination of Pegasys and Copegus alone in treatment-naïvepatients with chronic hepatitis C genotype 1 virus infection |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the pharmacokinetics of RO5190591 in combination with Pegasys and Copegus
To evaluate the viral resistance profile of RO5190591 in combination with Pegasys and Copegus |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
- Roche Clinical Repository (RCR)
objectives - Samples collected on a voluntary basis will be used for research purposes only to identify potential dynamic biomarkers that are predictive of response to RO5190591 treatment.
The objective is to better understand the potential relationships between the dose, safety and tolerability, and response to RO5190591 treatment and to understand the pathogenesis of HCV related diseases and associated AEs. Potential applications include these samples being assayed for cytokines/chemokines/other soluble immune modulators, gene expression, genetic variation, and marker(s) for manageable toxicity. Since the identification of new markers that correlate with disease activity and the efficacy or safety of treatment is rapidly developing, the definitive list of analytes remains to be determined.
Protocol version : see section A4 (since this substudy is associated to the main protocol)
- Intensive Pharmacokinetic Assessments
objectives : Intensive pharmacokinetic sub-study samples will be collected for measurement of RO5190591 (and its metabolites if assay is available) in approximately 20% of patients.
Protocol version : see section A4 (since this substudy is associated to the main protocol)
|
|
| E.3 | Principal inclusion criteria |
1. Age 18 years and older
2. Serologic evidence of CHC infection by an anti-HCV antibody test (current or historical)
3. Evidence of chronic hepatitis C infection > 6 months duration
4. Evidence of hepatitis C genotype 1 infection by molecular assay
5. Serum HCV RNA quantifiable at ≥ 50,000 IU/mL as demonstrated by the Roche COBAS TaqMan HCV Test
6. HCV treatment-naïve (i.e. have never received treatment for CHC, including but not
limited to IFN-based therapy, ribavirin, or other anti-viral agents with established or
perceived activity against the HCV virus)
7. Liver biopsy within the past 24 months showing clear absence of advanced fibrosis
or cirrhosis (as indicated in Appendix 1). Liver biopsy should be scored using one of
the scoring methods in Appendix 1.
8. Normal cardiac troponin I (cTnI) value at the screening visit (< 0.100 ng/mL)
9. Serum total bilirubin value at the screening visit within the reference range
10. Negative urine pregnancy test (for females of childbearing potential) documented
within the 24-hour period prior to the first dose of study drugs confirmed by a
negative serum pregnancy test collected within 24 hours prior to the first dose of
study drug. 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 following the last dose of RBV in
accordance with locally approved label for RBV
11. Willingness to give written informed consent and willingness to participate in and
comply with the study requirements |
|
| E.4 | Principal exclusion criteria |
1. Infection with any HCV genotype other than genotype 1 or an indeterminate or mixed genotype. Genotype 1 pts w indeterminate or mixed subtypes will be allowed
2. History of having received any IMP ≤ 3m prior to the 1st dose of study drug or the expectation that such drugs will be used during the study. Pts enrolled in this study cannot be enrolled in another study for either research, diagnostic or treatment purposes Pts 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 excl
4. + test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or anti-HIV Ab
5. History or other evidence of a medical condition associated with chronic liver disease other than HCV
6. Females who are pregnant or breast feeding
7. Male partners of females who are pregnant
8. BMI < 18 or ≥ 36
9. Absolute neutrophil count (ANC) < 1.5 x 103 / μL (< 1.5 x 109 /L)
10. Platelet count < 90 x 103 / μL (< 90 x 109 /L)
11. Hemoglobin (Hgb) concentration < 11 g/dL (< 110 g/L) in females or < 12 g/dL (<120 g/L)in males or any pt w a baseline increased risk for anemia or for whom anemia would be medically problematic
12. Serum creatinine level > 1.5* the upper limit of normal at screening
13. 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 6m
14. Hist of severe psychiatric disease, incl psychosis and/or severe depression, characterized by a suicide attempt, hospitalization for psychiatric disease, or a period of disability as a result of psychiatric disease. In add, pts w a concurrent psychiatric condition or history of a psychiatric condition that, in the opinion of the Inv and/or Psychiatrist, would compromise participation in this study
15. Hist of immunologically mediated disease
17. Poorly controlled hypertension, with a hist of poor adherence to antihypertensive therapy or screening or baseline blood pressure of systolic ≥ 160 mmHg and/or diastolic ≥100 mmHg
18. Type I or II diabetes with HbA1C > 8.5% at the Screening Visit
19. Hist or other evidence of chronic pulmonary disease associated with functional
limitation
20. Hist of severe cardiac disease. In add, pts w doc or presumed coronary artery disease, stable or unstable cardiovascular disease or cerebrovascular disease should not be enrolled
21. Pts w higher potential for QTC prolongation; defined by QTC ≥ 450 ms, or notable resting bradycardia < 50 beats/min, or notable resting tachycardia > 100 beats/min or personal or family history of congenital long QT syndrome or sudden death
22. Hist of uncontrolled severe seizure disorder
23. Evidence of an active or suspected cancer, or a history of malignancy where the risk of recurrence is ≥ 20% within 2y.
24. Hist of any systemic anti-neoplastic or immunomodulatory treatment (incl supraphysiologic doses of steroids and radiation) ≤ 6m prior to the 1st dose of study drug or the expectation that such treatment will be needed at any time during the study
25. Poorly controlled thyroid dysfunction
26. Hist or other evidence of a clinically relevant ophthalmologic disorder due to
diabetes mellitus or hypertension or history /other evidence of severe retinopathy
27. Hist of major organ transplantation with an existing functional graft
28. Hist or other evidence of severe illness, or any other conditions which would make the pt, in the opinion of the investigator, unsuitable for the study
29. Use of the following concomitant medications that may result in drug-drug
interaction. Exceptions will be made if the rationale is discussed and doc btw the Inv and the Sponsor.
• Any medications or herbal sup that are inhibitors of CYP3A4. These agents should be discontinued at least 7d or 5 half-lives (whichever is longer) b4 the 1st dose of RO5190591/placebo
• Any medications or herbal sup that are inducers of metabolic enzymes. These agents should be discontinued at least 14d or 5 half-lives (whichever is longer) before the 1st dose of RO5190591/placebo
30. Consumption of grapefruit, or Seville orange containing products or apple juice
within 3d b4 the 1st dose of RO5190591/placebo and while on treat w RO5190591/placebo
31. Evidence of excessive alcohol, drug or substance abuse (excluding marijuana use)
within 1y of 1st dose
32. Hist of allergy to ribavirin, pegylated interferons or other interferons |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary measure of efficacy is SVR defined as the percentage of patients with
undetectable HCV RNA as measured by the Roche COBAS TaqMan HCV Test
(detection limit = 15 IU/mL) 24 weeks after end of treatment (SVR-24; a single last HCV RNA undetectable ≥ 20 weeks after last dose). Patients without HCV RNA
measurements at the end of the 24-week treatment-free follow-up period will be
considered non-responders. This definition of SVR will be “SVR according to actual
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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
| Viral resistance, tolerability, Biomarkers analysis |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 8 |
| 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 | Yes |
| 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 last patient last visit. Last patient last visit is 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 (required for statistical analysis) 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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