Antifibrotic Activity Of GI262570 In Chronic Hepatitis C Subjects
Condition: Cirrhosis, Liver
MeSH terms: Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Cirrhosis
Intervention: GI262570 0.5 mg; GI262570 1.0 mg; Placebo
Intervention description: GI262570 0.5 mg; GI262570 1.0 mg; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Enrollment: 265.0
Sex: All
Minimum age: 40 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Hepatitis C liver fibrosis

Summary:

      The purpose of this study is to examine the safety and effectiveness of GI262570 compared to
      placebo (a pill that looks exactly like GI262570 but contains no active medicine) in
      improving specific tests that indicate the degree of liver fibrosis (scarring). Subjects who
      are enrolled in the study must have had prior treatment with interferon (either pegylated or
      standard interferon) plus ribavirin for at least 12 weeks to treat their hepatitis C, but
      either failed to clear the virus or didn't tolerate the treatment.
    

Eligibility criteria:

        Inclusion criteria:

          -  A subject will be eligible for inclusion in this study only if all of the following
             criteria apply:

          -  Age between 40 and 70 years, inclusive.

          -  Documented positive serology for HCV antibody by a second generation or higher assay.

          -  Serum HCV RNA positive and HCV viral Genotype 1 at pre-screening visit.

          -  Ishak fibrosis score of 2, 3 or 4.

          -  Failure to achieve sustained virologic response (SVR) with previous interferon
             (standard or pegylated) and ribavirin treatment administered at a minimum dose of 3mU
             three times weekly or equivalent, for at least 12 weeks. Reasons for failure may
             include failure to respond to treatment or intolerability to optimal treatment. Prior
             treatment with interferon/ribavirin must have been discontinued at least 11 months
             prior to the biopsy date.

          -  Male or female; a female is eligible to enter and participate in this study if she is
             of:

               1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant,
                  including any female who is post-menopausal); or,

               2. child-bearing potential, has a negative serum pregnancy test at screen, and
                  agrees to one of the following:

                    -  Complete abstinence from intercourse from 2 weeks prior to administration of
                       the study drug, throughout the study, and for a time interval after
                       completion or premature discontinuation from the study to account for
                       elimination of the investigational drug, (a minimum of 5 half-lives or
                       longer if the pharmacodynamic profile of the investigational drug warrants a
                       longer time period); or,

                    -  Female sterilization; or,

                    -  Has a male partner who is sterilized; or,

                    -  Implants of levonorgestrel; or,

                    -  Injectable progestogen; or,

                    -  Oral contraceptive (combined or progestogen only) , must be stable for 3
                       months prior to study entry; or,

                    -  Any intrauterine device (IUD) with published data showing that the lowest
                       expected failure rate is less than 1% per year (not all IUDs meet this
                       criterion); or,

                    -  Any other methods with published data showing that the lowest expected
                       failure rate for that method is less than 1% per year; or,

                    -  Barrier method only if used in combination with any of the above acceptable
                       methods.

          -  Availability and willingness of subject to provide written informed consent.

        Exclusion criteria:

        A subject will not be eligible for inclusion in this study if any of the following criteria
        apply:

          -  History of ascites, variceal hemorrhage, hepatic encephalopathy, spontaneous bacterial
             peritonitis or other signs of hepatic decompensation.

          -  Current or historical evidence suggestive of ischemic heart disease or other
             cardiovascular disease that in the investigator's opinion may adversely impact the
             safety of the subject during the conduct of the study. Evidence suggestive of
             cardiovascular disease may come from a number of sources, including clinical history,
             physical exam, electrocardiogram, laboratory testing, and radiographic procedures.

          -  New York Heart Association (NYHA) Functional Class 1, 2, 3, or 4 cardiac status

          -  Co-infection with HBV or HIV.

          -  Liver histology consistent with any other co-existing cause of chronic liver disease.

          -  Documented evidence of a hepatic mass lesion suspicious for hepatocellular carcinoma.

          -  Alpha-fetoprotein > 200ng/mL at pre-screening.

          -  Inadequate hematologic function defined by any of the following:

        Hemoglobin (<12.5 g/dL for men)(<12.0 g/dL for women)

        Absolute Neutrophil Count (ANC) (<1.0 x 10^9/L) Platelets (<130X/10^9/L)

          -  Inadequate renal function defined as:

        Serum creatinine (>1.5mg/dL (≥130mmol/L)) Calculated creatinine clearance as calculated by
        Cockcroft and Gault (<60mL/min)

          -  Serum ALT level ≥5 x ULN.

          -  Albumin <3.2g/dL.

          -  Total bilirubin >1.2 x ULN.

          -  Prothrombin time > 15 seconds or International normalized ratio (INR) > 1.3.

          -  Organ, stem cell, or bone marrow transplant.

          -  Serious concurrent medical illness that in the investigator's opinion might interfere
             with therapy. This includes significant systemic illnesses (other than liver disease)
             such as chronic pancreatitis.

          -  Active systemic autoimmune disorder.

          -  A pre-existing condition interfering with normal gastrointestinal anatomy or motility,
             and/or renal function that could interfere with the absorption, metabolism, and/or
             excretion of the study drugs.

          -  Other medical conditions that, in the investigator's opinion, might interfere with
             compliance with therapy, participation in the study or interpretation of results.

          -  Pregnancy (or lactation) or, in subjects capable of bearing children,
             inability/unwillingness to practice adequate contraception.

          -  Females of child-bearing potential (post-puberty) unwilling or unable to have
             pregnancy testing at any study visit.

          -  Therapy with systemic cytotoxic agents, immunomodulators, or immunosuppressive therapy
             requiring use of more than 5mg of prednisone (or its equivalent) per day.

          -  Therapy with a systemic antiviral agent (with the exception of prophylaxis or
             treatment of influenza or chronic HSV) within the past 30 days.

          -  Concurrent participation in another clinical trial in which the subject is or will be
             exposed to another investigational or a non-investigational drug or device within 30
             days of the screening visit.

          -  Current therapy or anticipated need for therapy with hypoglycemic drugs (e.g.,
             insulin, sulfonylurea or metformin).

          -  Known hypersensitivity to GI262570, or to any component of the GI262570 soft gelatin
             capsules, dispersion tablets or the sodium salt tablet or to PPARg agonists.

          -  A history of hepatotoxicity to TZDs and/or a history of severe edema or medically
             serious fluid-related events associated with the use of TZDs.

          -  Use of other PPAR agonists (e.g., rosiglitazone, pioglitazone) within 1 year from the
             start of dosing.

          -  Active alcohol abuse within the past 1 year.

          -  Use of illegal drugs in the past 1 year. 30a. Macular edema or history of macular
             edema.