Pharmacokinetic and Pharmacodynamic Study of IDN-6556 in ACLF

Study Overview
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Brief Summary
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The study will evaluate the pharmacokinetics, pharmacodynamics, safety and preliminary efficacy of IDN-6556 in subjects with cirrhosis of the liver who are hospitalized for more than 24 hours due to acute deterioration of liver function.

Official Title
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A Placebo-Controlled, Multicenter, Double-Blind, Randomized, Pharmacokinetic and Pharmacodynamic Trial of IDN-6556 in Subjects With Acute-on-Chronic Liver Failure

Conditions
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Acute on Chronic Hepatic Failure, Acute Liver Failure, Liver Cirrhosis, Acute Alcoholic Hepatitis

Intervention / Treatment
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* Drug: IDN-6556
* Other: 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 understand and comply with the requirements of the study Subjects with a clinical, radiological and/or histological diagnosis of cirrhosis Subjects having not required hospital admission within 4 weeks of screening for a complication of cirrhosis Subjects with an acute deterioration of liver function Subjects who meet one of the following criteria: Subjects with renal failure (defined as creatinine ≥ 2.0 to ≤ 3.4 mg/dL) Subjects with other single organ failure with i. Renal impairment (defined as an increase in creatinine of > 0.3 mg/dL from either an established prior Baseline level or if applicable, upon admission to hospital if prior level is unavailable; for inclusion, the creatinine level must be raised above normal levels), and/or ii. Hepatic encephalopathy grade I or II Subjects with two organ failures If a subject received steroids for alcohol-induced acute liver failure, he/she must be unresponsive to steroid therapy. Responsiveness is based on investigator discretion. 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 HIV Subjects with cirrhosis who develop decompensation at any time in the postoperative period following partial hepatectomy Subjects with evidence of uncontrolled infection defined as persistent bacterial culture positivity despite adequate antibiotic therapy Subjects with clinical evidence of disseminated intravascular coagulation Subjects with chronic and/or pre-existing kidney disease defined as eGFR (estimated glomerular filtration rate) of less than 30 mL/min for 3 months or longer Subjects who are hypotensive (defined as mean arterial pressure <70 mmHg) or require the use of inotropic support Subjects with evidence of significant and/or uncontrolled bleeding Subjects requiring mechanical ventilation 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 Subjects previously exposed to IDN-6556 History or presence of clinically concerning cardiac arrhythmias, or prolongation of Screening (pre-treatment) QT or QTc interval of > 480 milliseconds (msec)

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IDN-6556 5 mg<br>Dosed twice daily | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Experimental: IDN-6556 25 mg<br>Dosed twice daily | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Experimental: IDN-6556 50 mg<br>Dosed twice daily | Drug: IDN-6556<br> <br> * Other names: PF-03491390;|
| Placebo Comparator: Placebo<br>Dosed twice daily | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) | Primary endpoints for AUC_0-8, AUC_0 last, AUC_0-inf on Day 1 and Day 4 for the active treatment arms were analyzed. | 28 days | 
| Cmax | Primary endpoints forCmax on Day 1 and Day 4 for the active treatment arms were analyzed. | 28 Days | 
| Tmax & t1/2 Parameters | Primary endpoints for tmax & t1/2 on Day 1 and Day 4 for the active treatment arms were analyzed. | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Levels of CK18/M30 | Caspase-cleaved cytokeratin serum levels (CK18/M30) | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | 
| Levels of CK18/M65 | Caspase full-length cytokeratin serum levels CK18/M65 | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | 
| Levels of Caspase 3/7 RLU | Concentration of Caspase 3/7 Relative Light Units | Baseline, Day 2, Day 4, Day 7, Day 14, Day 21, and Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver Failure, Cirrhosis, Alcoholic Hepatitis