A Study of IDN-6556 in Subjects With Liver Cirrhosis

Study Overview
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Brief Summary
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This is a multicenter study to see if treatment with IDN-6556 can help improve the liver function of patients with liver cirrhosis with Model for End-Stage Liver Disease scores between 11-18.

Detailed Description
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Numerous studies have shown that caspase cleaved cytokeratin 18 (cCK18) is elevated in the serum of liver disease patients and has been associated with disease severity, thus associating both excessive apoptosis and caspase activity with disease. Studies have also shown that caspase cleaved cytokeratin 18 is generally elevated to an even greater degree in cirrhosis than in other liver diseases. In addition, increasing stages of cirrhosis from Child-Pugh A, Child-Pugh B to Child-Pugh C are associated with progressively higher levels of caspase cleaved cytokeratin 18. Therefore, it appears that apoptosis and caspase activity tend to correlate with the stage of cirrhosis. A caspase inhibitor like IDN-6556 could have clinical utility by reducing the rate of apoptosis in cirrhotic patients and potentially reduce the progression of disease as determined by clinical markers of progression.

Official Title
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A Multicenter, Double-Blind, Placebo Controlled Study to Evaluate the Safety, Tolerability and Efficacy of IDN-6556 in Subjects With Liver Cirrhosis

Conditions
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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 Clinical, radiological, or biochemical evidence of liver cirrhosis Model for End-Stage Liver Disease (MELD) Score of 11 to 18 during the Screening period 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 human immunodeficiency virus (HIV) Auto-immune hepatitis Subjects with evidence of uncontrolled infection, defined as persistent bacterial culture positivity despite adequate antibiotic therapy HCV infected subjects who are receiving or plan to receive anti-viral therapy during the study Untreated esophageal varices with high risk stigmata for hemorrhage Variceal hemorrhage within 3 months of Screening Ascites not adequately controlled on stable background medication Other non-liver organ failure Child-Pugh score of 10-15 (Child-Pugh C classification) Use of vasoactive drugs (at or within 3 months of Screening) that may impair hepatic blood flow Change in dose or regimen within 3 months of Screening of: Fibrates or statins Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE) inhibitor Use of chronic anticoagulation therapy including but not limited to Vitamin K/Factor Xa antagonists/inhibitors Use of the following drugs within 2 months of Screening: Systemic corticosteroids Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) Concomitant pancreatitis Active inflammatory bowel disease Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) Subjects with active or history of malignancies other than hepatocellular carcinoma (HCC) within Milan criteria or curatively treated skin cancer (basal cell or squamous cell carcinomas), unless adequately treated or in complete remission for five or more years

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>25 mg BID of IDN-6556 | Drug: IDN-6556<br>* 25 mg BID<br>* Other names: PF-03491390;|
| Placebo Comparator: Placebo<br>Placebo BID | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Month 3 in cCK18/M30 | Baseline, Month 3, and change between for cCK18/M30 | 3 months | 
| Change From Baseline at Month 3 in cCK18/M30 | Data was log-transformed for analysis purposes | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 3 in MELD Score | The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease and uses the subject's values for total bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. MELD is calculated according to the following formula: MELD = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43 MELD scores are reported as whole numbers, so the result of the equation above is rounded. Notes: If the patient has been dialyzed twice within the last 7 days, then the value for serum creatinine used should be 4.0. Any value less than one is given a value of 1 (i.e. if bilirubin is 0.8, a value of 1.0 is used) to prevent the occurrence of scores below 0 (the natural logarithm of 1 is 0, and any value below 1 would yield a negative result). The higher the MELD score the more severe the disease state. | 3 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Cirrhosis, Hepatic Cirrhosis