Multiple Oral Doses of BI 207127 NA in Treatment naïve and Treatment-experienced Hepatitis C Virus (HCV)-Infected Patients

Safety, Antiviral Activity, and Pharmacokinetics of Multiple Oral Doses of BI 207127 NA Administered q8H for 5 Days as Monotherapy, a Randomised, Double-blind, Placebo Controlled Study

The purpose of this study was to investigate antiviral activity, safety and pharmacokinetics of 5 days of monotherapy with BI 207127 in HCV genotype 1 (GT1) infected patients. Both treatment-naïve patients and patients previously treated with peginterferon and ribavirin were included. In addition, the effect of study medication was examined in a group of patients with liver cirrhosis.

Inclusion Criteria:

• Adults from 18 - 70 years
• Male OR female with documented hysterectomy OR menopausal female with last menstrual period at least 12 months prior to screening
• Written informed consent consistent with International Conference on Harmonization/Good Clinical Practice and local legislation given prior to any study procedures
• Chronic HCV infection demonstrated by positive HCV immunoglobulin G Antibody
• HCV genotype 1 which has to be confirmed by central laboratory test before Visit 2
• For non-cirrhotic cohorts: Liver biopsy obtained within the last 36 months consistent with HCV infection showing minimal to mild liver fibrosis and without cirrhosis (Ishak or Metavir grade ≤ 2). For cirrhotic cohorts, previous liver biopsy or Fibroscan consistent with liver cirrhosis performed at any time before screening
• HCV RNA load > 100,000 IU RNA per ml serum at screening

Exclusion Criteria:

• All fertile males not willing to use an adequate form of contraception (condom, sterilisation at least 6 months post operation) in case their partner is of childbearing potential and is not using an adequate form of contraception (hormonal contraceptives, oral or injectable/ implantable, intra-uterine device)

• Patients who have been treated with at least one dose of any HCV-polymerase inhibitor for acute or chronic hepatitis C infection

• Any other or additional plausible cause for chronic liver disease, including the presence of other viruses known or suspected to cause hepatitis

• Decompensated liver disease within past 12 months, as indicated by variceal bleeding, ascites, encephalopathy, Prothrombin or International Normalized Ratio (INR) prolonged to >1.7 x upper limit of normal (ULN), serum bilirubin > 2 mg/dl or albumin < 3.5 g/dl (i.e. Child-Pugh grade B, score > 7)

• For non-cirrhotic cohorts: Any previous liver biopsy consistent with cirrhosis. For cirrhotic cohorts: Any liver biopsy or fibroscan result from last 2 years excluding liver cirrhosis.

• Positive test for human immunodeficiency virus (HIV) or hepatitis B antigen at screening

• Current alcohol or drug abuse, or history of the same, within the past six (6) months. Exception: Occasional use of cannabis is not an exclusion criterion. The investigator must however instruct the patient that consumption of cannabis is not allowed during the treatment period.

• Any concurrent disease (cardiovascular, pulmonary, renal, haematological, neurological, psychiatric, immunologic, metabolic or endocrine dysfunction) if clinically significant based on the investigator's medical assessment at screening. A clinically significant disease is defined as one which in the opinion of the investigator may either put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study. Exclusion is also necessary for any pre-existing cardiac abnormality by history.

• Clinically significant abnormalities at screening ECG, including but not limited to a QTc longer than 435 msec, Pulse Rate > 240 msec at baseline and any bundle branch block pattern, but not necessarily non-specific T wave abnormalities

• History of malignancy (except for previously cured squamous cell or basal cell carcinoma)

• Patients treated with any interferon (IFN) (approved or investigational) or Peg-IFN and/or Ribavirin within 3 months prior to screening

• Planned or concurrent usage of any other pharmacological therapy including any antiviral therapy or vaccination from 7 days before treatment and during treatment

• Usage of any investigational drug within thirty (30) days prior to enrolment or 5 halflives, whichever is longer; or the planned usage of an investigational drug during the course of the current study

• Known hypersensitivity to drugs or excipients

• Patients with any one of the following laboratory values at screening:

  • Alanine transaminase (ALT) > 3x ULN, local lab

  • Aspartate aminotransferase (AST) > 3x ULN, local lab

  • Total bilirubin > 1.5x ULN, local lab, unless predominantly conjugated and reflecting Gilbert's disease

  • Alkaline phosphatase > 1.5x ULN, local lab

  • Prothrombin time (INR) > 1.5x ULN, central lab

  • Creatinine > 1x ULN, local lab

  • Urine protein / creatinine ratio > 0.3 g protein / g creatinine, central lab

  • Alpha-1-microglobulin / creatinine in urine > 1x ULN, central lab

  • Platelet count < 100,000 / mm3, central lab

  • White Blood cell count < 2000 cells/mm3, central lab

  • Absolute neutrophile count < 1500 cells, central lab

  • Hemoglobin < 12 g/dL, central lab

  • For patients with liver cirrhosis:

    • ALT > 5x ULN, local lab
    • AST > 5x ULN, local lab
    • Platelet count < 70,000 / mm3, central lab

• Patients with any clinically significant laboratory abnormalities based on the investigator's medical assessment at screening

• Positive urine test for drug abuse at screening

• Prior randomisation into this trial

• Inability to comply with the protocol

• Patients with ongoing or historical photosensitivity or recurrent rash

• Alpha fetoprotein value (AFP) > 100 ng/ml; if AFP is > 20 and ≤ 100 ng/ml, patients can be included if liver cancer is excluded by a current imaging study (i.e. ultrasound, computer tomography scan or magnetic resonance imaging)