Dose Ranging of GSK2336805 in Combination Therapy

GSK2336805 is a novel hepatitis C virus (HCV) non-structural 5A (NS5A) inhibitor being developed for the treatment of chronic HCV infection. This Phase II, multicenter, parallel-group, randomized, dose-ranging study will assess the safety and tolerability, antiviral activity, and pharmacokinetics of GSK2336805 at 2 dose levels (40 and 60 mg) in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA) in approximately 100 treatment-naïve subjects with chronic genotype 1 HCV infection.

In a separate nonrandomized single-arm cohort, up to 15 treatment-naïve subjects with genotype 4 chronic HCV infection will be enrolled in parallel at the dose level of 60 mg of GSK2336805.

Subjects with chronic genotype 1 hepatitis C virus (HCV) infection will be randomly assigned on a 2:2:1 basis to 1 of 3 treatment arms: T40 (GSK2336805 40 mg and PEG + RIBA) or T60 (GSK2336805 60 mg and PEG + RIBA) or PEG + RIBA and telaprevir (PRT). Randomization will be stratified by interleukin 28B (IL28B) rs12979860 status (C/C versus carriage of the T allele), HCV genotype (1a vs. 1b), and plasma HCV Ribonucleic Acid (RNA) (\<800,000 IU/mL versus ≥800,000 IU/mL).

An additional nonrandomized single-arm cohort of subjects with chronic genotype 4 HCV infection will be enrolled in parallel. A maximum of 15 genotype 4 subjects will receive GSK2336805 60 mg and PEG + RIBA. The purpose of this cohort is to further characterize the antiviral activity of GSK2336805 in subjects with chronic genotype 4 HCV infection. The schedule of assessments for the genotype 4 subjects will be the same as for the genotype 1 subjects. Recruitment of the genotype 4 subjects may be terminated when the target sample of genotype 1 subjects have been randomized.

Subjects in a GSK2336805 treatment arm who achieve extended rapid virologic response (eRVR) will receive a total of 24 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 12 weeks PEG + RIBA). Subjects who are HCV detectable at Week 4 and then undetectable at Week 12 will receive a total of 48 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 36 weeks PEG + RIBA). Subjects in the telaprevir treatment control arm will be managed according to the current product label for treatment-naïve subjects.

Subjects who complete treatment will undergo follow-up monitoring for 24 weeks after completion of therapy. At the end of the 24-week follow-up visit, subjects will have completed their participation in the study. The total duration of the study will be 48 weeks for subjects who achieve eRVR at Week 12 and up to 72 weeks for subjects who do not achieve eRVR at Week 12.

Eligibility Criteria:
Inclusion Criteria:

* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Male or female aged 18 to 70 years of age, inclusive, at Screening.
* Genotype 1 or genotype 4 hepatitis C virus (HCV) infection as assessed by Versant HCV Genotype assay 2.0 (LiPA).
* Chronic HCV infection documented by at least 1 measurement of serum HCV RNA greater than or equal to 100,000 IU/mL measured during Screening by the COBAS High Pure/COBAS TaqMan HCV Test v2.0 and at least one of the following:
* A positive anti-HCV antibody, HCV RNA, or HCV genotype test at least 6 months prior to Baseline (Day 1) together with positive HCV RNA and anti-HCV antibody tests at the time of Screening; or
* A positive HCV RNA test and anti-HCV antibody test at the time of Screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic hepatitis C disease, such as the presence of fibrosis).
* Naïve to all HCV antiviral treatment(s), including, but not limited to, immunomodulatory and nucleoside/nucleotide treatments for chronic HCV infection.
* Agree to interleukin 28B (IL28B) genotyping.
* A subject, who, in the opinion of the investigator, is an appropriate candidate for pegylated interferon alpha-2a (PEG)/ribavirin (RIBA)/protease inhibitor combination therapy for genotype 1 subjects and PEG/RIBA combination therapy for genotype 4 subjects.
* Body mass index \>18 kg/m2 but not exceeding 36 kg/m2.
* A liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of noncirrhotic as judged by a local pathologist (defined as Knodell less than or equal to 3, Metavir less than or equal to 2, Ishak less than or equal to 4, or Batts and Ludwig less than or equal to 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis. If no recent (\<36 months) liver biopsy is available, a study-qualifying biopsy must be performed prior to Baseline (Day 1).
* All fertile males and females must use 2 forms of effective contraception between them during treatment and during the 24 weeks after treatment ends.
* Females, is eligible to enter and participate in the study if of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) and includes any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy) or has had a bilateral tubal ligation or is postmenopausal (demonstrate total cessation of menses for greater than 1 year).
* Females, is eligible to enter and participate in the study if of childbearing potential and has a negative urine or serum pregnancy test at Screening and within the 24-hour period prior to the first dose of study medication and completely abstains from intercourse for 2 weeks before exposure to the study medication, throughout the clinical study, and for 24 weeks after completion or premature discontinuation from this study or uses 2 of the following acceptable methods of contraception throughout the clinical study and for 24 weeks after completion or premature discontinuation from this study:
* Any intrauterine device with a documented failure rate of \<1% per year
* Double-barrier contraception (condom, diaphragm, or cervical cap used with spermicidal jelly)
* Male partner who is sterile prior to the female subject's study entry and is the sole sexual partner for that female
* Any other contraceptive method with a documented failure rate of \<1% per year
* Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening.

Exclusion Criteria:

* Positive test at Screening visit for hepatitis B surface antigen (HBsAg) or antihuman immunodeficiency virus antibody
* History of any other clinically significant chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, Wilson's disease, 1-antitrypsin deficiency, alcoholic liver disease, \>Grade 1 nonalcoholic steatohepatitis, and toxin exposures). Subjects with Gilbert's syndrome who otherwise meet all inclusion/exclusion criteria are eligible.
* History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease
* Positive results on urine screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription)
* History of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation program)
* Screening visit electrocardiogram corrected QT (QTc) interval value \>450 ms and/or clinically significant electrocardiogram findings
* Personal or family history of Torsade de Pointes findings
* Pregnant or nursing
* Male with a female partner who is pregnant
* Abnormal hematological and biochemical parameters, including:
* Neutrophil count \<1500 cells/mm3 (or \<1250 cells/mm3 for African American/Black subjects)
* Hemoglobin \<11 g/dL in females or \<12 g/dL in males
* Creatinine greater than or equal to 1.5 × the upper limit of normal (ULN)
* Estimated creatinine clearance less than or equal to 50 mL/min (as calculated using the Cockcroft-Gault formula)
* Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase greater than or equal to 5 × ULN
* Total bilirubin greater than or equal to 2.0 × ULN (except subjects with Gilbert's syndrome)
* Albumin less than or equal to 3.0 g/dL
* Platelet count less than or equal to 90,000/mm3
* History of major organ transplantation with an existing functional graft
* Thyroid dysfunction not adequately controlled
* History of suicide attempt or hospitalization for depression in the past 5 years
* History of any current (within 6 months) severe or poorly controlled psychiatric disorder
* Subjects who have had a severe or poorly controlled psychiatric disorder more than 6 months ago but less than 5 years ago are eligible for study participation but must be assessed and followed (if recommended) by a mental health professional.
* History or current evidence of immunologic disorder; cardiac or pulmonary disease; seizure disorder; or cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study.
* Treated with herbal or natural remedies with antiviral activity within 30 days of the baseline visit or has a history of having received any systemic antineoplastic or immunomodulatory treatment (including mycophenolate mofetil, thymosin alpha, supraphysiologic doses of steroids \>10 mg/day and radiation) within 6 months of the baseline visit or expects that such treatment will be needed at any time during the study.
* Participated in a clinical study with an investigational drug, biologic, or device within 3 months prior to the first dose administration.
* History of a known allergy to antiviral medications, including telaprevir, pegylated interferon alpha-2a (PEG), ribavirin (RIBA), or any excipient in the investigational product or history of drug or other allergy that, in the opinion of the investigator, contradicts participation.
* Requires prohibited medications