Dose Ranging of GSK2336805 in Combination Therapy
Condition: Hepatitis C, Chronic
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis
Intervention: GSK2336805 40 mg; GSK2336805 60 mg; Pegylated interferon alpha-2a; Ribavirin; Telaprevir
Intervention description: 20 mg tablet, round, 10-mm diameter, white to off-white, no markings; 30 mg tablet, round, 10-mm diameter, white to off-white, no markings; 180 microgram per 0.5 mL prefilled syringe for single use; 200-mg tablet, capsule-shaped, light blue, film-coated, and debossed with "200" on 1 side and the logo "3RP" on the other side; 375 mg film-coated tablet
Intervention MeSH terms: Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 286.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Genotype 4; GSK2336805; pegylated interferon; telaprevir; Genotype 1; chronic hepatitis C; ribavirin; NS5A inhibitor; hepatitis C virus (HCV) infection

Summary:

      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.
    

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