Antifibrotic Activity Of GI262570 In Chronic Hepatitis C Subjects

GlaxoSmithKline265 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Enrollment

265

Conditions

Cirrhosis, Liver

Interventions

GI262570 0.5 mgDRUG

GI262570 0.5 mg

GI262570 1.0 mgDRUG

GI262570 1.0 mg

PlaceboDRUG

Placebo

Eligibility

Sex: ALLMin age: 40 YearsMax age: 70 Years

Medical Language ↔ Plain English

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.

Locations (121)

Outcomes

Primary Outcomes

Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52

A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. The immunohistochemical marker assessed was smooth muscle alpha-actin (aSMA). Sections of the liver biopsies were stained by standard immunocytochemical techniques using a monoclonal antibody to smooth muscle actin with 'very intense purple' as the detection chromogen. This gives a reddish-purple color to the activated stellate cells, which strongly contrasts with the rest of the tissue. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area.

Time frame: Baseline and Week 52

Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis

A percutaneous liver biopsy was obtained at the screening visit and at Week 52. A new liver biopsy at the screening visit was not taken in the event that a previous liver biopsy taken within 120 days of the Baseline /Day 1 visit (day of first dose), and the tissue block was available. Morphometric analysis was performed using specimens stained with Sirius red and computerized image analysis. Sirius red was used to stain extracellular collagen in liver sections. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing. The values are presented as proportion of positive area over total area.

Time frame: Baseline and at Week 52

Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52

In ranked assessment (fibrosis and necroinflammation), available slides from each participant were evaluated as to whether one slide presents a globally more benign histopathology or whether the matched slides comprise globally equivalent histologic patterns. Subsequent data analysis revealed whether slides scored (within matched pairs of slides) as more benign occurred in different proportions of the Week 52 liver biopsies, according to treatment group. The number of participants with paired biopsies was based on the number with a Rank Assessment.

Data from ClinicalTrials.gov

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Secondary Outcomes

Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52

Progression was defined as an increase by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.

Time frame: Week 52

Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52

Regression was defined as a decrease by at least one point in the fibrosis score. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.

Time frame: Week 52

Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52

No change was defined as having the same score at both Baseline and at Week 52. Score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The number of participants with paired biopsies is based on the number with an Ishak Fibrosis score.

Time frame: Week 52

Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52

Ishak score ranged from 0 to 6 (higher score indicates greater fibrosis). 0: No fibrosis, 1: Fibrous expansion of some portal areas, with or without short fibrous septa, 2: Fibrous expansion of most portal areas, with or without short fibrous septa, 3: Fibrous expansion of most portal areas with portal to portal bridging, 4: Fibrous expansion of portal areas with marked bridging, 5: Marked bridging with occasional nodules (incomplete cirrhosis), 6: Cirrhosis, probable or definite. The necroinflammatory score is the combined score for necrosis and inflammation domains and ranged from 0 (best) to 14 (worst). Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter.

Time frame: Screening and Week 52

Mean Change From Screening in Metavir Scores at Week 52

Metavir activity score ranged from 0 to 3 (higher score indicates severe symptoms of necrosis). 0: Piecemeal necrosis (PMN) absent and lobular necrosis (LN) absent or slight, 1: PMN slight and LN moderate, 2: PMN moderate and LN severe, 3: PMN severe. Metavir fibrosis score ranged from 0 to 4 (higher score indicates severe symptoms of necrosis). 0: No fibrosis, 1: Portal fibrosis without septa, 2: Portal fibrosis with septa, 3: Septal fibrosis without cirrhosis, 4: Cirrhosis. Change from screening was calculated as the post screening assessment minus the screening assessment for a given parameter.

Time frame: Screening and Week 52

Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52

FibroTest was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha-2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase. FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and \>= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase. ActiTest was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and \>= 0.61 indicates severe necrosis. Day 1 value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.

Time frame: Baseline and Week 52

Mean Change From Baseline in Serum ALT Levels

ALT was assessed as per upper limit of normal where the normal range was 0-48 international units per liter. Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.

Time frame: Baseline and Week 52

Mean Change From Baseline in Measures of Insulin Resistance

Insulin resistance was measured using Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), Belfiore Insulin Sensitivity Index (ISI) and Quantitative Insulin Sensitivity Check Index (QUICKI). HOMA-IR = fasting plasma insulin\*fasting plasma glucose / 22.5 and ISI = 2 / \[(fasting plasma glucose from the participant / fasting plasma glucose normal reference range)\*( fasting plasma insulin from the participant / fasting plasma insulin normal reference range) + 1\] and QUICKI = 1/(log\[fasting plasma Insulin\] + log\[fasting plasma glucose\]). Day 1 (before dosing) value was considered to be as Baseline value. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.

Time frame: Baseline and Week 52

Median Change From Baseline in Serum ALT Over Time

Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)

Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52

Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.

Time frame: Baseline and Week 52

Median Change From Baseline in Serum HCV RNA Levels Over Time

Serum for HCV RNA levels were collected at pre-screen, Baseline, Week 28, Week 52, and at the 4 week follow up visit. Value at Day 1 visit (day of first dose) was considered as Baseline. Change from Baseline was calculated as the post Baseline assessment minus the Baseline assessment for a given parameter. If either the Baseline or on-treatment value was missing, the change from Baseline value was also set to missing.

Time frame: Baseline and up to 4 weeks post-treatment (52 weeks)

Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2

Samples for Week 2 serial group were collected at 0 (pre-morning dose)1, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 hour post-morning dose. Initially the doses selected for the study were 0.5 mg twice daily and 1.0 mg twice daily. However, because of implementation of Amendment 4, the dose regimen was reduced to half the original dosing resulting in dose once daily.