A Study of IDN-6556 in Cirrhotic Subjects With Portal Hypertension

Study Overview
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Brief Summary
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This is an open-label pilot study to evaluate the safety, tolerability, and efficacy of IDN-6556 in treating portal hypertension in subjects with liver cirrhosis.

Detailed Description
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Studies in patients with liver disease have demonstrated that cCK18 is elevated in the serum of patients and has been associated with disease severity. Studies have also shown that cCK18 is generally elevated to a higher 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. This suggests that apoptosis and caspase activity are associated with the severity of disease. IDN-6556 and its ability to inhibit inflammation and apoptosis may have a beneficial impact on both the dynamic and structural components associated with the pathogenesis of portal hypertension in cirrhosis.

Official Title
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An Open-Label Pilot Trial to Evaluate the Safety, Tolerability and Efficacy of IDN-6556 in Cirrhotic Subjects With Portal Hypertension

Conditions
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Liver Cirrhosis, Hepatic Cirrhosis, Portal Hypertension

Intervention / Treatment
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* Drug: IDN-6556


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 Evidence of portal hypertension as evidenced by any of the following: Splenomegaly, on imaging and/or clinical evaluation, with platelet count of <120,000 at study entry, or Presence of small sized varices on screening endoscopy and/or collateral circulation on imaging, or Presence of medium/large varices that have never bled and have been obliterated with endoscopic ligation Portal hypertension defined as a hepatic venous pressure gradient (HVPG) >5 mmHg at Screening 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: Decompensated cirrhosis as defined by the presence of overt ascites (requiring diuretics), overt encephalopathy (requiring specific therapy), or history of variceal hemorrhage. Known infection with HIV Hepatic failure defined as total bilirubin ≥12 mg/dL Other non-liver organ failure, including: Renal failure defined as creatinine ≥ 2.0 mg/dL Cerebral failure defined as hepatic encephalopathy grade III or IV Coagulation failure defined as INR ≥ 2.5 or platelets ≤ 20x109/L Hemodynamic requirement for inotropic support 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; examples include but are not limited to: β-blockers, including carvedilol Nitrates Vasopressin (or analogues) Phosphodiesterase inhibitors (prescribed daily for pulmonary hypertension; p.r.n. use for erectile dysfunction is permitted) 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 the following drugs within 2 months of Screening: Systemic corticosteroids Pentoxifylline Known or suspected use of illicit drugs or drugs of abuse (allowed if medically prescribed or indicated) Concomitant pancreatitis Evidence of portal vein thrombosis on Doppler ultrasound of the portal vasculature Active inflammatory bowel disease Diagnosed or suspected systemic lupus erythematosus (SLE) and/or rheumatoid arthritis (RA) Autoimmune hepatitis Hepatitis C Virus (HCV) infected subjects receiving or planning on receiving anti-viral therapy during the course of the study Hepatitis B Virus (HBV) infected subjects who have been on stable anti-HBV therapy for less than 3 months Hepatocellular carcinoma (HCC) at entry into the study Active non-liver malignancies other than curatively treated skin cancer (basal cell or squamous cell carcinomas) History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QT or QTc interval of >480 milliseconds (msec) Significant systemic or major illness other than liver disease, including coronary artery disease, cerebrovascular disease, pulmonary disease, renal failure, serious psychiatric disease, that, in the opinion of the Investigator would preclude the subject from participating in and completing the study Any subject that has received any investigational drug or device within 30 days of dosing or who is scheduled to receive another investigational drug or device in the course of the study If female, known pregnancy, or has a 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IDN-6556 - Overall population<br>Overall evaluable population treated with IDN-6556 25 mg twice daily | Drug: IDN-6556<br>* 25 mg BID<br>* Other names: PF-013491390;|
| Experimental: IDN-6556 - Subgroup with Baseline HVPG < 12 mmHg<br>Subgroup for patients with Baseline HVPG < 12 mmHg that have been treated with IDN-6556 25 mg twice daily | Drug: IDN-6556<br>* 25 mg BID<br>* Other names: PF-013491390;|
| Experimental: IDN-6556 - Subgroup Baseline HVPG ≥ 12 mmHg<br>Subgroup for patients with Baseline HVPG ≥ 12 mmHg that have been treated with IDN-6556 25 mg twice daily | Drug: IDN-6556<br>* 25 mg BID<br>* Other names: PF-013491390;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic Venous Pressure Gradient (HVPG) | Mean change of HVPG [mmHg] from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Baseline to Day 28/EOT (end of treatment) | 
| cCK18/M30 | Absolute Mean Change of caspase-cleaved cytokeratin serum levels (cCK18/M30); the statistical analysis is based on the mean change in log-transformed cCK18/M30 from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Change from Baseline to Day 28/EOT | 
| Change in cCK18/M30 | Median change of caspase-cleaved cytokeratin serum levels (cCK18/M30) from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Baseline to Day 28/EOT (end of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Alanine Aminotransferase (ALT) | Median change of ALT from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Baseline to 28 days/EOT | 
| Change in Aspartate Aminotransferase (AST) | Median change of AST from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Baseline to 28 days/EOT | 
| Concentration of Caspase 3/7 RLU | Median change of concentration of Caspase 3/7 Relative Light Units from Baseline to Day 28/EOT (end of treatment) for IDN-6556 | Baseline to 28 days/EOT | 

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