A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV

Phase 2

Completed

Conditions: Liver Fibrosis
Hepatic Fibrosis
Liver Cirrhosis
Hepatic Cirrhosis

Interventions: Drug: Placebo
Drug: IDN-6556

Registration Number: NCT02138253

Lead Sponsor: Conatus Pharmaceuticals Inc.

Brief Summary: This is a double-blind, multicenter study involving patients with chronic HCV infection who had a liver transplantation; developed HCV-related liver fibrosis and/or incomplete cirrhosis; achieved a sustained virologic response (SVR) following anti-HCV therapy; but still have fibrosis and/or incomplete cirrhosis on liver biopsy to see if treatment with IDN-6556 is better than placebo in reversing or stopping the progression of the damage to the new liver caused by HCV.

Detailed Description: There are data to suggest that with eradication of the HCV virus, improvements in liver fibrosis can be seen in the post-transplant population. However, amelioration of inflammatory activity, and deceleration of fibrosis progression is a gradual process over the course of many years. This placebo-controlled study is designed to evaluate the effects of IDN-6556, compared to placebo, on markers of apoptosis and inflammation, and liver histology.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

Inclusion Criteria

Male or female subjects of minimum adult legal age (according to local laws for signing the informed consent document), able to provide written informed consent, and able to understand and willing to comply with the requirements of the study
History of orthotopic liver transplantation for HCV-induced liver disease
Diagnosis of HCV infection (HCV-RNA detectable in serum) and liver fibrosis and/or incomplete cirrhosis status post liver transplantation, and achieved a sustained virologic response (SVR) with anti-viral HCV treatment within 18 months of Day 1
Liver fibrosis on liver histology as read by central histopathologist of Ishak F2 to F6 within three months of Day 1 (Up to 15 subjects with an Ishak score of F6 can be enrolled)
Willingness to utilize two reliable forms of contraception (for both males and females of childbearing potential) from Screening to one month after the last dose of study drug

Exclusion Criteria

Known infection with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV)
History of renal transplant and/or severe renal impairment defined as eGFR (estimated glomerular filtration rate) of less than 30 mL/min/1.73 m2
Evidence of tumor burden >Milan criteria, or evidence of micro- or macrovascular invasion in explanted liver
Hepatocellular carcinoma (HCC) at entry into the study
Concurrent sirolimus (rapamycin) use
History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of > 480 milliseconds (msec)
Subjects with diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA)
If female: known pregnancy, positive urine or serum pregnancy test, or lactating/breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo BID
IDN-6556	IDN-6556	IDN-6556 25 mg BID

Primary Outcome Measures

Name	Time	Method
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	24 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite Since the primary analysis used multiple imputation methodology, the numerator and denominator varied across 20 imputations.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only)	24 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score	12 months	At least a one stage reduction from baseline in Ishak Fibrosis Stage. Score F0 No fibrosis F1 Fibrous expansion of some portal areas, with or without short fibrous septa F2 Fibrous expansion of most portal areas, with or without short fibrous septa F3 Fibrous expansion of most portal areas, with occasional portal to portal bridging F4 Fibrous expansion of portal areas, with marked bridging (portal to portal as well as portal to central) F5 Marked bridging (portal to portal and/or portal to central) with occasional nodules (incomplete cirrhosis) F6 Cirrhosis probable or definite
Alanine Aminotransferase (ALT) - Change From Baseline	Baseline and 24 months	Liver function laboratory parameter
Aspartate Aminotransferase (AST) Change From Baseline	Baseline and 24 months	Liver function laboratory parameter
Caspase 3/7 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function
cCK18/M30 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function.
flCK18/M65 Change From Baseline	Baseline and 24 months	Mechanistic biomarker of liver function
Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis	24 months	The Ishak modification of Knodell histological activity index was determined by liver biopsy. Interface hepatitis * 0 = None * 1 = Mild (local, few portal areas) * 2 = Mild/moderate (focal, most portal areas) * 3 = Moderate (continuous around \<50% of tracts or septa) * 4 = Severe (continuous around \>50% of tracts or septa)
Ishak Modification of Knodell Histological Index - Confluent Necrosis	24 months	The Ishak modification of Knodell histological activity index will be determined by liver biopsy. The four items and their categorizations scores include: • confluent necrosis * 0 = None * 1 = Focal confluent necrosis * 2 = Zone 3 necrosis in some areas * 3 = Zone 3 necrosis in most areas * 4 = Zone 3 necrosis + occasional portal-central bridging * 5 = Zone 3 necrosis + multiple portal-central bridging * 6 = Panacinar or multiacinar necrosis
Ishak Modification of Knodell Histological Index - Parenchymal Injury	24 months	The Ishak modification of Knodell histological activity index will be determined by liver biopsy. • parenchymal injury (focal lytic necrosis, apoptosis and focal inflammation) * 0 = None * 1 = One focus or less per 10× objective * 2 = Two to four foci per 10× objective * 3 = Five to ten foci per 10× objective * 4 = More than ten foci per 10× objective
Ishak Modification of Knodell Histological Index - Portal Inflammation	24 months	Portal inflammation * 0 = None * 1 = Mild, some or all portal areas * 2 = Moderate, some or all portal areas * 3 = Moderate/marked, all portal areas * 4 = Marked, all portal areas

Trial Locations

Locations (35): Loma Linda University Medical Center
🇺🇸
Loma Linda, California, United States
UCLA Pfleger Liver Institute
🇺🇸
Los Angeles, California, United States
Piedmont Atlanta Hospital
🇺🇸
Atlanta, Georgia, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
John Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
Rutgers New Jersey Medical School
🇺🇸
Newark, New Jersey, United States
University of Pennsylvania Milton Hershey Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
Temple University Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
Albert Einstein Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
Southern California Research Center
🇺🇸
Coronado, California, United States
Scripps Clinic
🇺🇸
La Jolla, California, United States
Ochsner Clinic
🇺🇸
New Orleans, Louisiana, United States
Saint Louis University
🇺🇸
Saint Louis, Missouri, United States
University of Cincinnati Physicians Company
🇺🇸
Cincinnati, Ohio, United States
Indiana University
🇺🇸
Indianapolis, Indiana, United States
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
Liver Associates of Texas, PA
🇺🇸
Houston, Texas, United States
University of Texas Health Science Center at Houston
🇺🇸
Houston, Texas, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
Johns Hopkins Sibley Memorial Hospital
🇺🇸
Washington, District of Columbia, United States
Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
University of Florida
🇺🇸
Gainesville, Florida, United States
University of Miami
🇺🇸
Miami, Florida, United States
University of Chicago Medicine
🇺🇸
Chicago, Illinois, United States
Tulane Health Science Center
🇺🇸
New Orleans, Louisiana, United States
University of Louisville
🇺🇸
Louisville, Kentucky, United States
Henery Ford Health System
🇺🇸
Detroit, Michigan, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Baylor All Saints Medical Center
🇺🇸
Fort Worth, Texas, United States
VAMC/Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Bon Secours Mary Immaculate Hospital
🇺🇸
Newport News, Virginia, United States
Bon Secours St. Mary's Hospital of Richmond
🇺🇸
Richmond, Virginia, United States
McGuire DVAMC
🇺🇸
Richmond, Virginia, United States
University of Washington Harborview Medical Center
🇺🇸
Seattle, Washington, United States
University of Kansas Medical Center
🇺🇸
Kansas City, Kansas, United States