| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 study the effects of dose and duration of the HCV polymerase inhibitor prodrug (RO5024048) in combination with PEG-IFN and RBV versus the currently approved combination of PEG-IFN and RBV (SOC) in treatment-naive patients with chronic hepatitis C genotype 1 and 4 virus infection. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of HCV polymerase inhibitor prodrug (RO5024048) in combination with PEG-IFN and RBV versus the currently approved combination of SOC
- To determine virologic response at defined time points (Week 4, 12, 24, 48 and 60).
- To evaluate the pharmacokinetics of RO4995855 when RO5024048 is administered in combination with SOC
- To evaluate the resistance profile of RO5024048 in combination with SOC
- To evaluate safety and efficacy of open-label HCV polymerase inhibitor Prodrug
(RO5024048) in combination with SOC in the subset of patients who only received currently approved combination of SOC (Group E) and who did not demonstrate an early virologic response (Treatment Failures) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Age 18 – 65 years
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 or 4 infection by molecular assay
5.Serum HCV RNA quantifiable at ≥50,000 IU/mL as demonstrated by the Roche COBAS TaqMan HCV Test
6.Chronic liver disease consistent with chronic hepatitis C infection on a biopsy obtained within the past 24 months (36 months for patients with cirrhosis or incomplete/transition to cirrhosis), using one of the scoring methods in Appendix 2
7.Patients with cirrhosis or incomplete/transition to cirrhosis must have an abdominal ultrasound, computerized tomography (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 (< 100 µg/L)
8.Compensated liver disease (Child-Pugh Grade A clinical classification only)
9.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 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
10.Willingness to give written informed consent and willingness to participate in and comply with the study requirements
|
|
| E.4 | Principal exclusion criteria |
1.Females who are pregnant or breast feeding
2.Male partners of females who are pregnant
3.Body mass index (BMI) < 18 or ≥ 36
4. Infection with any HCV genotype other than genotype 1 or 4. Genotype 1 and 4
patients with indeterminate or mixed subtypes will be allowed
5.History of having received any IFN, PEG-IFN, RBV, viramidine, levovirin, polymerase or protease inhibitors or other investigational anti-HCV at any 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
6.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
7.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
8.Positive test at screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or anti HIV Ab
9.History or other evidence of a medical condition associated with chronic liver disease other than HCV (e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, α1 antitrypsin deficiency, metabolic liver disease, alcoholic liver disease, and/or toxin exposure)
10.Absolute neutrophil count (ANC) < 1.5 x103 /µL (< 1.5 x 109/L)
11.Platelet count < 90 x103/µL (< 90 x 109/L)
12.Hemoglobin concentration < 12 g/dL (120 g/L) in females or < 13 g/dL (130 g/L) in males or any patient with a baseline increased risk for anemia (e.g., thalassemia, sickle cell anemia, spherocytosis, history of gastrointestinal bleeding) or for whom anemia would be medically problematic
13.Presence of schistocytes on peripheral blood smear
14.Serum amylase or lipase levels > 1.5 times the upper limit of normal
15.Serum total bilirubin ≥ 2 times the upper limit of normal
16. History of pre-existing renal disease. Patients with a history of nephrolithiasis will
be allowed.
17.Estimated creatinine clearance of ≤ 80 mL/min (≤ 1.34 mL/sec), calculated by the Cockcroft-Gault formula
18.Serum creatinine > 1.5 times the upper limit of normal
19.Greater than trace hematuria (≥1+ or >10 RBC/HPF, unless related to menstruation)
20. Microproteinuria with protein/creatinine ratio ≥ 0.3 (≥ 33.89 mg/mmol) as
determined by urine chemistry test (see Appendix 6 for details)
21. One or more of the following: (i) poorly controlled hypertension, OR (ii) poor
adherence to antihypertensive therapy, OR (iii) current use of > 2 antihypertensive
agents required, OR (iv) screening or baseline blood pressure ≥ 140 mmHg for
systolic OR (v) ≥ 90 mmHg for diastolic blood pressure
22.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
23.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
24.History of immunologically mediated disease (e.g., vasculitis, cryoglobulinemia, inflammatory bowel disease, idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic anemia, scleroderma, severe psoriasis (defined as affecting > 10% of the body, where 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, etc) or positive results for ANA (≥1:320) or ANCA (≥1:80)
25.History or other evidence of decompensated liver disease or a Child-Pugh Grade B or higher Appendix 1. Coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminemia, ascites, and bleeding from esophageal varices are conditions consistent with decompensated liver disease
26.Type I or II diabetes mellitus with HbA1C > 7
27.History or other evidence of chronic pulmonary disease associated with functional limitation
28.History of severe cardiac disease (e.g. NYHA Functional Class III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable angina or other significant cardiovascular disease). In addition, patients with documented or presumed coronary artery disease, stable or unstable cardiovascular disease or cerebrovascular disease should not be enrolled
Please see all exclusion criteria (1-37) in the protocol section 4.3. |
|
| 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”.
Additional analyses will be performed using the definition of SVR defined as the percentage of patients with undetectable HCV RNA as measured by Roche COBAS TaqMan HCV test at or after week 44 (≥study day 309) for treatment groups A, B and C with total treatment duration of 24 weeks or at or after week 68 (≥ study day 477) for treatment groups with total treatment duration of 48 weeks. This definition of SVR will be “SVR according to scheduled treatment period”.
All primary and secondary analyses of SVR will be performed using both definitions. Subgroup analysis and explorative analysis for SVR will be performed only for “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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability, Virologic response, Optional biomarker sample repository samples |
|
| 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 |
| Dose and Duration Finding Study, Group F is open-label |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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
| |
| 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 | 8 |
| 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 | 8 |
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