Japanese Phase II Study of SB-497115-GR in Hepatitis C Virus Infected Patients

Non-randomised, Open Label, Multi-centre Phase II Study to Assess the Efficacy and Safety of SB-497115-GR in Thrombocytopenic Subjects With Chronic Hepatitis C and Compensated Liver Cirrhosis.

The purpose of this study is to assess the ability of SB-497115-GR to raise platelet counts in thrombocytopenic patients with hepatitis C virus (HCV) infection (platelet count <80,000 /μL, suggestive of compensated cirrhosis) to a level desirable to initiate antiviral therapy and to assess the ability of SB-497115-GR to maintain platelet counts at a level sufficient to minimise dose reductions of pegylated interferon (Peg-IFN) and ribavirin (RBV) therapy with the expectation that a lower rate of Peg-IFN dose reduction and omission will translate to a higher rate of sustained viral response.

Inclusion Criteria:

Subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned, as well as provided a written consent.

• A subject age between ≥20 and <75 years at time of informed consent.
• A subject who applies to one of the following:

Female subject with non-childbearing potential [i.e., physiologically incapable of becoming pregnant, who: has had a hysterectomy, or had a bilateral oophorectomy (ovariectomy), or had a bilateral tubal ligation, or is post-menopausal for greater than one year].

Female subject with childbearing potential, has a negative urine or serum pregnancy test at screening and within the 24-hour period prior to the first dose of SB-497115-GR, and completely abstains from intercourse or agree to use two of the following acceptable methods of contraception for 14 days before exposure to SB-497115-GR, throughout the clinical trial, and for 24 weeks after completion or premature discontinuation from the study.

Intrauterine device or intrauterine system that meets the effectiveness criteria as stated in the product label.

Male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject.

Double-barrier contraception (condom with spermicidal jelly, or diaphragm with spermicide).

Male subject with childbearing potential partner completely abstains from intercourse or agree to use condom and diaphragm with spermicide.

• Subjects who were diagnosed as hepatitis C or compensated liver cirrhosis (Child-Pugh class A) without hepatic encephalopathy, or ascites. If there is a clear cirrhosis, treatment should be given with care as there is a potential of progressing to liver failure.
• Subjects who, in the opinion of the investigator, are appropriate candidates for Peg-IFN and RBV combination therapy for 48 weeks.
• HCV positive by TaqMan test at screening.
• Subject who fulfil all the organ functions below.

Items Values Platelet <80,000 /μL Haemoglobin ≥12.0 g/dL* Absolute neutrophil count (ANC) ≥1500 /μL* Creatinine clearance >50 mL/minute Total bilirubin <2.0 mg/dL Albumin >3.0 g/dL Prothrombin time >60%

*If the investigators consider the values are sufficient to give Peg-IFN/RBV, then a subject can be enrolled upon consulting the Medical Monitor.

Exclusion Criteria:

• Subject who relapsed or did not respond after 48 weeks of Peg-IFN/RBV therapy had been given with sufficient dose previously.
• Subject with history of IFN (including Peg-IFN) therapy or Peg-IFN/RBV therapy, but could not been treated with optimal Peg-IFN/RBV therapy due to the reasons other than thrombocytopenia.
• Subject who received IFN therapy (including Peg-IFN), antiviral therapy (excluding oseltamivir phosphate, etc.), immuno-modulatory treatment, radiotherapy or phlebotomy within 3 months (90 days) prior to the first dose of SB-497115-GR.
• Treatment with an investigational drug within 30 days prior to the first dose of SB-497115-GR or 5 half-lives of that investigational drug (whichever is longer).
• Subject with decompensated liver disease.
• Chronic liver disease other than chronic hepatitis C (e.g., autoimmune hepatitis, alcohol-induced hepatitis, drug-induced hepatitis, etc.).
• Subject with idiopathic thrombocytopenic purpura or active autoimmune disease.
• Subject who have had a malignancy diagnosed and/or treated within the past 5 years.
• Subjects who require endoscopic treatment for varices or documented history of clinically significant bleeding from oesophageal or gastric varices.
• Any disease condition associated with active bleeding or requiring anticoagulation with heparin or warfarin.
• Subject with serious cardiac, cerebrovascular, chronic pulmonary disease or interstitial lung disease, or documented history of any of these diseases.
• Pre-existing cardiac disease (congestive heart failure in New York Heart Association Grade III/IV), or arrhythmias known to involve the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTcF >450 msec or if with bundle brunch block, QTcF >480 msec.
• Subject with depression, psychiatric disorder requiring treatment or suicidal ideation or suicide attempt history, or history of these.
• Subject with uncontrolled hypertension (≥160 mmHg systolic or ≥100 mmHg diastolic).
• Subject with diabetes mellitus that can not be controlled by treatment.
• Thyroid dysfunction not adequately controlled.
• Subjects with haemoglobinopathies.
• History or current condition of seizure disorder.
• Subject who was positive for Human Immunodeficiency Virus (HIV) antibody or Hepatitis B Virus (HBV) antigen.
• Subject with arterial or venous thrombosis history or evidence of portal vein thrombosis on abdominal imaging (e.g., by computerized tomography or magnetic resonance imaging) within 3 months.
• History of alcohol/drug abuse or dependence.
• History of platelet clumping that prevents reliable measurement of platelet counts.
• Subjects planning to have cataract surgery.
• History of major organ transplantation.
• Known hypersensitivity to SB-497115-GR ingredients, IFN (including Peg-IFN), nucleoside analogues or biological agents (i.e., vaccines).
• Pregnant or nursing women or a male subject with pregnant partner.