Chronic hepatitis C subjects with hepatic fibrosis who have failed prior antiviral therapy
Conditions
Interventions
Product Name: GI262570
Product Code: GI262570
Pharmaceutical Form: Tablet
INN or Proposed INN: farglitazar
Current Sponsor code: GI262570
Concentration unit: mg milligram(s)
Concentration type: equal
Sponsors
GlaxoSmithKline R&D
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age between 40 and 70 years. 2. Documented positive serology for HCV antibody by a second generation or higher assay. 3. Serum HCV RNA positive and HCV viral Genotype 1 at pre-screening visit. 4. Ishak fibrosis score of 3 or 4. 5. 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 12 months prior to the baseline visit. 6. Male or female; a female is eligible to enter and participate in this study if she is of: a. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); or, b. 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. 7. Availability and willingness of subject to provide written informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. History of ascites, variceal hemorrhage, hepatic encephalopathy, spontaneous bacterial peritonitis or other signs of hepatic decompensation. 2. History of ischemic heart disease. 3. New York Heart Association (NYHA) Functional Class 1, 2, 3 or 4 cardiac status (Appendix 2). 4. Co-infection with HBV or HIV. 5. Liver histology consistent with any other co-existing cause of chronic liver disease. 6. Documented evidence of a hepatic mass lesion suspicious for hepatocellular carcinoma. 7. Alpha-fetoprotein > 200ng/mL at pre-screening. 8. Inadequate hematologic function. 9. Inadequate renal function. 10. Serum ALT level >5 x ULN. 11. Albumin 1.2 x ULN. 13. Prothrombin time > 15 seconds or International normalized ratio (INR) > 1.3. 14. Organ, stem cell, or bone marrow transplant. 15. 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. 16. Active systemic autoimmune disorder. 17. 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. 18. Other medical conditions that, in the investigator’s opinion, might interfere with compliance with therapy, participation in the study or interpretation of results. 19. Pregnancy (or lactation) or, in subjects capable of bearing children, inability/unwillingness to practice adequate contraception. 20. Females of child-bearing potential (post-puberty) unwilling or unable to have pregnancy testing at any study visit. 21. Therapy with systemic cytotoxic agents, immunomodulators, or immunosuppressive therapy requiring use of more than 5mg of prednisone (or its equivalent) per day. 22. Therapy with a systemic antiviral agent (with the exception of prophylaxis or treatment of influenza or chronic HSV) within the past 30 days. 23. 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. 24. Current therapy or anticipated need for therapy with hypoglycemic drugs (e.g., insulin, sulfonylurea or metformin). 25. Known hypersensitivity to GI262570, or to any component of the GI262570 soft gelatin capsules, dispersion tablets or the sodium salt tablet or to PPAR agonists. 26. 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. 27. Use of other PPAR agonists (e.g., rosiglitazone, pioglitazone) within 1 year from the start of dosing. 28. Active alcohol abuse within the past 1 year. 29. Use of illegal drugs in the past 1 year.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To describe the safety and efficacy of two doses of GI262570 treatment in chronic hepatitis C subjects with Genotype 1 infection, who have failed prior anti-HCV therapy, in improving immunohistochemical markers of fibrogenesis (markers of HSC activation) over the course of the study as compared with placebo-treated subjects;Secondary Objective: Changes in liver histology over 52 weeks of therapy with GI262570 or placebo. Relationships between serum markers of hepatic fibrosis and treatment with GI262570. Serum proteins related to extracellular matrix deposition and breakdown, signalling pathways which may regulate HSC and those involved in hepatic inflammation. The effect of GI262570 on serum HCV RNA. GI262570 plasma PK parameters in HCV-infected adults following dosing every 12 hours. Relationships between plasma PK parameters and pharmacodynamic (PD) measures (e.g., Ishak fibrosis score, ALT and/or other biomarkers) collected throughout the study. The molecular profile of whole blood samples and/or liver biopsy tissue (transcriptome analyses) to identify markers associated with hepatic fibrosis progression, severity or response to GI262570. The effect of GI262570 on insulin resistance and incident diabetes in subjects with HCV.;Primary end point(s): • Change from baseline in liver biopsy immunohistochemical markers of HSC activation and collagen synthesis. • Change from baseline in fibrosis as quantified by morphometric image analysis. • Ranked histological assessment of the paired biopsies (Baseline versus Week 52). • Assessment of safety and tolerability of GI262570 in comparison with placebo: • Nature and frequency of adverse events and laboratory abnormalities. • Changes over time in laboratory parameters and vital signs. • Incidence of fluid retention events (weight gain, edema, hemodilution, concomitant medications). • Clinically significant ECG abnormalities. | — |
Countries
Czech Republic, Germany
Outcome results
None listed