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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Multicenter, Double-Blind, Randomized Trial of IDN-6556 in Subjects Who Had Hepatitis C Virus (HCV) Reinfection and Liver Fibrosis Following Orthotopic Liver Transplantation for Chronic HCV Infection and Who Subsequently Achieved a Sustained Virologic Response Following Anti-HCV Therapy

Conditions
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Liver Fibrosis, Hepatic Fibrosis, Liver Cirrhosis, Hepatic Cirrhosis

Intervention / Treatment
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* Drug: IDN-6556
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IDN-6556<br>IDN-6556 25 mg BID | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Placebo Comparator: Placebo<br>Placebo BID | Drug: Placebo<br>* Placebo control<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score | 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only) | 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 | 24 months | 
| Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score | 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 | 12 months | 
| Alanine Aminotransferase (ALT) - Change From Baseline | Liver function laboratory parameter | Baseline and 24 months | 
| Aspartate Aminotransferase (AST) Change From Baseline | Liver function laboratory parameter | Baseline and 24 months | 
| Caspase 3/7 Change From Baseline | Mechanistic biomarker of liver function | Baseline and 24 months | 
| cCK18/M30 Change From Baseline | Mechanistic biomarker of liver function. | Baseline and 24 months | 
| flCK18/M65 Change From Baseline | Mechanistic biomarker of liver function | Baseline and 24 months | 
| Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis | 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) | 24 months | 
| Ishak Modification of Knodell Histological Index - Confluent Necrosis | 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 | 24 months | 
| Ishak Modification of Knodell Histological Index - Parenchymal Injury | 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 | 24 months | 
| Ishak Modification of Knodell Histological Index - Portal Inflammation | 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 | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver transplant, hepatitis C, liver fibrosis, hepatic fibrosis, liver cirrhosis, hepatic cirrhosis