Antifibrotic Activity Of GI262570 In Chronic Hepatitis C Subjects

NCT00244751 | Completed Phase 2 Results

• 1 other identifier: FBX104114
• Study Type: interventional
• Target: 265
• Locations: 14 countries
• Sites: 121

Brief 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.

Conditions

Cirrhosis, Liver

Keywords

Hepatitis C liver fibrosis

Outcome Measures

Primary Outcomes (9)

• 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.

  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.

  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.

  Week 52

• Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)

  AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment.

  Up to 4 weeks post treatment (52 weeks)

• Number of Participants With Abnormal ECG Findings

  A standardized 12-lead ECGs were recorded at pre-screening, and pre-dose, at Baseline/Day 1, Weeks 16, 34, and 52 or withdrawal and at the 4 week follow-up visit. Any conditions such as bundle branch block, repolarization, depolarization, abnormal sinus rhythms, atrial fibrillation etc. are considered to be clinically abnormal findings.

  Up to 4 weeks post-treatment (52 weeks)

• Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time

  Clinical laboratory parameters: Alkaline phosphatase, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total bilirubin, Cholesterol, Carbon dioxide content/Bicarbonate (CO2/HCO3), Creatinine, Glucose, Hemoglobin, Potassium, Low density lipid (LDL) cholesterol, Lymphocytes, Sodium, Segmented neutrophils, Platelet count, White blood cell (WBC) count were assessed for change in grade toxicities. Toxicities were graded as grade 1 to grade 4 in increasing order of severity of toxicity. Thus grade 4 indicating severe toxicity. Only those parameters with grade 3 and 4 toxicities are presented.

  Up to 4 weeks post-treatment (52 weeks)

• Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP)

  SBP and DBP readings were taken at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. 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.

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

• Mean Change From Baseline in Heart Rate

  Heart rate assessment were done at pre-screening, pre-dose after 10 minutes of rest, at Baseline/Day 1, weeks 2, 4, 10, 16, 22, 28, 34, 40, 46, and 52 or WD and at the 4 week follow-up visit. 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 be missing.

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

• Number of Participants With Fluid Retention Events

  Fluid retention event was one of the AEs reported. AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

  Up to 4 weeks post-treatment (52 weeks)

Secondary Outcomes (19)

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

  Week 52

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

  Week 52

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

  Week 52

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

  Screening and Week 52

• Mean Change From Screening in Metavir Scores at Week 52

  Screening and Week 52

Study Arms (3)

GI262570 0.5 mg

EXPERIMENTAL

Participants received GI262570 0.5 milligrams (mg) tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52.

Drug: GI262570 0.5 mg

GI262570 1.0 mg

EXPERIMENTAL

Participants received GI262570 1.0 mg tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52.

Drug: GI262570 1.0 mg

Placebo

PLACEBO COMPARATOR

Participants received matching placebo tablet once daily approximately 30 minutes prior to breakfast for 52 weeks. Participant received their morning dose at the site on Weeks 2, 16, 28, 40, and 52.

Drug: Placebo

Interventions

GI262570 0.5 mg DRUG

GI262570 0.5 mg

GI262570 0.5 mg

GI262570 1.0 mg DRUG

GI262570 1.0 mg

GI262570 1.0 mg

Placebo DRUG

Placebo

Placebo

Eligibility Criteria

• Age: 40 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
• 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,

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (121)

GSK Investigational Site

Birmingham, Alabama, 35294-0005, United States

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GSK Investigational Site

Tucson, Arizona, 85719, United States

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GSK Investigational Site

North Little Rock, Arkansas, 72117, United States

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GSK Investigational Site

Bakersfield, California, 93301, United States

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GSK Investigational Site

La Jolla, California, 92024, United States

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Los Angeles, California, 90048, United States

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GSK Investigational Site

Los Angeles, California, 90095, United States

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Newport Beach, California, 92663, United States

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Pasadena, California, 91105, United States

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Sacramento, California, 95825, United States

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San Clemente, California, 92673, United States

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San Francisco, California, 94121, United States

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Santa Clara, California, 95051, United States

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Englewood, Colorado, 80113, United States

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Washington D.C., District of Columbia, 20010, United States

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Fort Lauderdale, Florida, 33308, United States

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Miami, Florida, 33136, United States

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Orlando, Florida, 32804, United States

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Sarasota, Florida, 34243, United States

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Atlanta, Georgia, 30033, United States

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Atlanta, Georgia, 30308, United States

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GSK Investigational Site

Atlanta, Georgia, 30309, United States

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Marietta, Georgia, 30060, United States

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Honolulu, Hawaii, 96817, United States

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Indianapolis, Indiana, 46202, United States

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Iowa City, Iowa, 52242, United States

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Louisville, Kentucky, 40202, United States

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Lutherville-Timonium, Maryland, 21093, United States

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Boston, Massachusetts, 02111, United States

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Boston, Massachusetts, 02114, United States

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Boston, Massachusetts, 02215, United States

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Worcester, Massachusetts, 01655, United States

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Ann Arbor, Michigan, 48109, United States

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Detroit, Michigan, 48202, United States

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St Louis, Missouri, 63104, United States

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Binghamton, New York, 13901, United States

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Manhasset, New York, 11030, United States

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New York, New York, 10003, United States

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New York, New York, 10021, United States

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New York, New York, 10029, United States

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New York, New York, 10032, United States

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Syracuse, New York, 13210, United States

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The Bronx, New York, 10468, United States

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Chapel Hill, North Carolina, 27599, United States

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Durham, North Carolina, 27710, United States

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Cincinnati, Ohio, 45219, United States

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Cincinnati, Ohio, 45267-0595, United States

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Cleveland, Ohio, 44195, United States

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Tulsa, Oklahoma, 74104, United States

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Hershey, Pennsylvania, 17033-0850, United States

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Lancaster, Pennsylvania, 17604-3200, United States

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Dallas, Texas, 75390-8887, United States

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Houston, Texas, 77030, United States

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San Antonio, Texas, 78215, United States

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Charlottesville, Virginia, 22908, United States

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Fairfax, Virginia, 22031, United States

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Richmond, Virginia, 23249, United States

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Richmond, Virginia, 23298, United States

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Herston, Queensland, 4029, Australia

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Camperdown, Victoria, Australia

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Clayton, Victoria, 3168, Australia

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Fitzroy, Melbourne, Victoria, 3065, Australia

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Heidelberg, Victoria, 3084, Australia

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Melbourne, Victoria, 3004, Australia

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Calgary, Alberta, T2N 4N1, Canada

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Vancouver, British Columbia, V5Z 1H2, Canada

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Victoria, British Columbia, V8V 3P9, Canada

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Winnipeg, Manitoba, R3E 3P4, Canada

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Halifax, Nova Scotia, B3H 2Y9, Canada

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London, Ontario, N6A 5A5, Canada

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Ottawa, Ontario, K1H 8L6, Canada

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Toronto, Ontario, M5G 1X5, Canada

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Toronto, Ontario, M5G 2N2, Canada

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Toronto, Ontario, M5T 2S8, Canada

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Montreal, Quebec, H2X 3J4, Canada

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Brno-Bohunice, 625 00, Czechia

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Hradec Králové, 500 12, Czechia

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Prague, 140 21, Czechia

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Prague, 169 02, Czechia

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Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

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Heidelberg, Baden-Wurttemberg, 69120, Germany

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Tübingen, Baden-Wurttemberg, 72076, Germany

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Erlangen, Bavaria, 91054, Germany

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Frankfurt am Main, Hesse, 60590, Germany

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Hanover, Lower Saxony, 30625, Germany

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Bonn, North Rhine-Westphalia, 53127, Germany

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Düsseldorf, North Rhine-Westphalia, 40225, Germany

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Münster, North Rhine-Westphalia, 48149, Germany

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Homburg, Saarland, 66421, Germany

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Leipzig, Saxony, 04103, Germany

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GSK Investigational Site

Halle, Saxony-Anhalt, 06120, Germany

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Berlin, 13353, Germany

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GSK Investigational Site

Hamburg, 20246, Germany

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GSK Investigational Site

Haifa, 31096, Israel

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GSK Investigational Site

Jerusalem, 91120, Israel

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Nazareth, 16100, Israel

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GSK Investigational Site

Petah Tikva, 49100, Israel

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GSK Investigational Site

Rehovot, 76100, Israel

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GSK Investigational Site

Tel Aviv, 64239, Israel

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GSK Investigational Site

Bandar Tun Razak, Cheras, 59100, Malaysia

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GSK Investigational Site

Kepong, 68100, Malaysia

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GSK Investigational Site

Auckland, 1001, New Zealand

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GSK Investigational Site

San Juan, 00909-1711, Puerto Rico

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GSK Investigational Site

Bucharest, 021105, Romania

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GSK Investigational Site

Bucharest, 022328, Romania

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GSK Investigational Site

Cluj-Napoca, Cluj, 400162, Romania

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GSK Investigational Site

Moscow, 105229, Russia

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GSK Investigational Site

Moscow, 115516, Russia

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GSK Investigational Site

Moscow, 121170, Russia

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GSK Investigational Site

Moscow, 129110, Russia

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GSK Investigational Site

Saint Petersburg, Russia

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GSK Investigational Site

Singapore, 169608, Singapore

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GSK Investigational Site

Daegu, 700-721, South Korea

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GSK Investigational Site

Pusan, 602-739, South Korea

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GSK Investigational Site

Seoul, 135-710, South Korea

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GSK Investigational Site

Seoul, 138-736, South Korea

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GSK Investigational Site

Seoul, 150-713, South Korea

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GSK Investigational Site

Kaohsiung City, 80708, Taiwan

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GSK Investigational Site

Kaohsiung City, 833, Taiwan

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GSK Investigational Site

Taipei, 112, Taiwan

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GSK Investigational Site

Taoyuan District, 333, Taiwan

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MeSH Terms

Conditions

Liver Cirrhosis

Interventions

farglitazar

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 25, 2005
• First Posted: October 27, 2005
• Study Start: November 2, 2005
• Primary Completion: March 13, 2008
• Study Completion: March 13, 2008
• Last Updated: December 11, 2017
• Results First Posted: December 11, 2017

Record last verified: 2017-11

Locations

CA (11); PR (1); AU (6); RU (5); RO (3); DE (14); KR (5); TW (4); US (58); CZ (4); MY (2); NZ (1); SG (1); IL (6)