Clinical trial NCT00244751: Antifibrotic Activity Of GI262570 In Chronic Hepatitis C Subjects
Official title: A Double-Blind, Randomized, Placebo-Controlled Multi-Center, Phase II Parallel Dose-Ranging Study to Assess the Antifibrotic Activity of GI262570 in Chronic Hepatitis C Subjects With Hepatic Fibrosis Who Have Failed Prior Antiviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cirrhosis, Liver
Keywords: Hepatitis C liver fibrosis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2005-10-27
Enrollment: 265
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Mean Change From Baseline in Liver Biopsy Immunohistochemical Marker of Hepatic Stellate Cell (HSC) Activation and Collagen Synthesis at Week 52
timeFrame: Baseline and Week 52
measure: Mean Change From Baseline in Fibrosis as Quantified by Morphometric Image Analysis
timeFrame: Baseline and at Week 52
measure: Number of Participants With Ranked Histological Assessment of the Paired Biopsies at Week 52
timeFrame: Week 52
measure: Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 4 weeks post treatment (52 weeks)
measure: Number of Participants With Abnormal ECG Findings
timeFrame: Up to 4 weeks post-treatment (52 weeks)
measure: Number of Participants With Change in Toxicities Grades 3 and 4 of Laboratory Parameters Over Time
timeFrame: Up to 4 weeks post-treatment (52 weeks)
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DSP)
timeFrame: Baseline and up to 4 weeks post-treatment (52 weeks)
measure: Mean Change From Baseline in Heart Rate
timeFrame: Baseline and up to 4 weeks post-treatment (52 weeks)
measure: Number of Participants With Fluid Retention Events
timeFrame: Up to 4 weeks post-treatment (52 weeks)
Secondary outcomes:
measure: Number of Participants Progressing at Least 1 Point on the Ishak Fibrosis Score at Week 52
timeFrame: Week 52
measure: Number of Participants Regressing at Least 1 Point on the Ishak Fibrosis Score at Week 52
timeFrame: Week 52
measure: Number of Participants Whose Ishak Fibrosis Score Remains Unchanged at Week 52
timeFrame: Week 52
measure: Mean Change From Screening in Total Ishak Score (Necroinflammatory Score and Fibrosis Score) at Week 52
timeFrame: Screening and Week 52
measure: Mean Change From Screening in Metavir Scores at Week 52
timeFrame: Screening and Week 52
measure: Mean Change From Baseline in Serum FibroSure (FibroTest/ActiTest) Score at Week 52
timeFrame: Baseline and Week 52
measure: Mean Change From Baseline in Serum ALT Levels
timeFrame: Baseline and Week 52
measure: Mean Change From Baseline in Measures of Insulin Resistance
timeFrame: Baseline and Week 52
measure: Median Change From Baseline in Serum ALT Over Time
timeFrame: Baseline and up to 4 weeks post-treatment (52 weeks)
measure: Mean Change From Baseline in Serum Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Levels at Week 52
timeFrame: Baseline and Week 52
measure: Median Change From Baseline in Serum HCV RNA Levels Over Time
timeFrame: Baseline and up to 4 weeks post-treatment (52 weeks)
measure: Area Under the Plasma Concentration-time Curve During One Dosing Interval of Length 'Tau' (AUC [0-tau]) of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: Dose Normalized (DN) AUC (0-tau) of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: Apparent Clearance Following Oral Dosing (CL/F) of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: Maximum Observed Concentration (Cmax), Minimum Observed Concentration (Cmin) of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: DN Cmax of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: Terminal Elimination Half-life (T1/2), Time to First Quantifiable Concentration (Tlag) and Time to Cmax (Tmax) of GI262570 on Week 2
timeFrame: 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 on Week 2
measure: Volume of Distribution Expressed as a Function of Bioavailability (V/F) of GI262570
timeFrame: 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 on Week 2
measure: GI262570 Serum Concentrations on Week 2, 16, 28, 40, and Week 52
timeFrame: Weeks 2, 16, 28, 40 and 52
Other outcomes:
Locations:
city: Birmingham
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facility: GSK Investigational Site
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state: Baden-Wuerttemberg
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country: Germany
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state: Baden-Wuerttemberg
city: Tuebingen
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state: Bayern
city: Frankfurt
country: Germany
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state: Hessen
city: Hannover
country: Germany
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state: Niedersachsen
city: Bonn
country: Germany
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city: Duesseldorf
country: Germany
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state: Nordrhein-Westfalen
city: Muenster
country: Germany
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state: Nordrhein-Westfalen
city: Homburg
country: Germany
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state: Saarland
city: Halle
country: Germany
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state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
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city: Haifa
country: Israel
facility: GSK Investigational Site
city: Jerusalem
country: Israel
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city: Nazareth
country: Israel
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country: Israel
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city: Rehovot
country: Israel
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city: Tel-Aviv
country: Israel
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city: Daegu
country: Korea, Republic of
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city: Pusan
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Bandar Tun Razak, Cheras
country: Malaysia
facility: GSK Investigational Site
city: Kepong
country: Malaysia
facility: GSK Investigational Site
city: Auckland
country: New Zealand
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Bucharest
country: Romania
facility: GSK Investigational Site
city: Cluj-Napoca, Cluj
country: Romania
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Saint-Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Singapore
country: Singapore
facility: GSK Investigational Site
city: Kaohsiung
country: Taiwan
facility: GSK Investigational Site
city: Kaohsiung
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taoyuan
country: Taiwan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: