A Multi-Center, Randomized, Double-Blind, Multiple Ascending Dose, Placebo-Controlled, Parallel Group 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic of the HCV Nucleoside Inhibitor RO5428029 in Healthy Subjects (Part A), and in Chronic Hepatitis C Genotype 1 Infected Patients (Part B).

The actual recommended treatment for chronic hepatitis C genotype I (PEG-IFN in
combination with ribavirin) has suboptimal results ( only 42%-52% of patients
achieving virus resistance.
In addition, there are significant safety and tolerability limitations
associated with interferon based treatments and presently, there is
no treatment for patients who are unable to tolerate or are contraindicated for
PEGIFN/RBV therapy. Consequently, there is a substantial need to improve
therapeutic
options for patients

Primary
1. To evaluate the safety, tolerability and pharmacokinetic
properties of RO5428029 in healthy subjects and chronic
hepatitis C genotype 1 infected patients.
2. To evaluate pharmacodynamics (viral load response) of
RO5428029 in chronic hepatitis C genotype 1 patients.

Secondary
To monitor the resistance profile of RO5428029 and evaluate
potential relationship of baseline susceptibility of the virus with
antiviral response in chronic hepatitis C genotype 1 patients.

Exploratory Objectives
The Roche Clinical Repository (RCR) is a centrally administered
facility for the long term storage of human biological specimens
including body fluids, solid tissues and derivatives thereof (e.g.
DNA, RNA proteins/ peptides). Specimens stored in the RCR will
be used to:
1. Study the association of biomarkers with efficacy and/ or
adverse events associated with medicinal products; and/ or
2. Increase our knowledge and understanding of disease
biology; and/or develop biomarker or diagnostic assays;
3. Establish the performance characteristics of these assays.

Up to 4 additional cohorts may be enrolled to explore alternative
BID doses and/or once daily doses depending on the plasma viral
load decline observed at Day 7 in Cohort B1. Doses in Part B will
not exceed 2000 mg BID

The total duration of the study for each patient will be up to 107
days, comprised of:

Screening
Up to 90 days (Days -90 to -3)

Study Treatment Duration
Up to 7 days (in clinic period starts Day -2 to Day 8)

Safety Follow-Up
7-10 days after the last dose

The total number of confinement days for patients in Part B of the
study will be 9 days

Proposed dosing schedule:
Cohort B1: 1000 mg BID/ 7 days
Cohort B2: to be decided /7 days
Cohort B3: to be decided /7 days
Cohort B4: to be decided /7days
Cohort B5: to be decided 7days

The doses in this study are adaptive in nature, and only the first
dose is fixed (i.e. 500 mg BID in Part A). Subsequent doses will
be better defined based on the safety, PK and PD from previous
cohorts. The dose selected for each subsequent cohort in each part
maybe as specified or lower based upon the results from previous
cohorts.
The maximum dose will not exceed 2000 mg BID.

- The patient is not allowed to eat and drink from 4 hours before the screening
and from 10 pm on the night of the study day.he/she is not allowed to eat..
- hospitalisation
- physical examination (with blood pressure measurement and ECG)
- blood and urine tests
- Sexually active men whose partner can become pregnant or is breastfeeding
have to use a double barrier contraceptive method during the study and up to 90
days after the last dose (such as the pill or an intra-uterine device plus
condom/cap and spermicidal gel).
- limited use of alcohol/drugs/tabac/medication
- urine has to be collected at home till 2 days after leaving the hospital

In previous studies conducted on healthy volunteers this study medicine was
well tolerated and the following side effects were observed: headache,
sleepiness and cold.