A Study of IDN-6556 in Subjects With Liver Cirrhosis (LC)

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

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.

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis; Hepatic Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: IDN-6556

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90048
      • Cedar-Sinai Medical Center
    • San Diego, California, United States, 92093
      • Univeristy of California, San Diego
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Georgia
    • Atlanta, Georgia, United States, 30309
      • Piedmont Atlanta Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Cente
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Mt. Sinai School of Medicine
    • New York, New York, United States, 10016
      • NYU Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Physicians Company, LLC
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Einstein Healthcare Network
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Baylor All Saints Medical Center
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Baylor St. Luke's Medical Center
    • Houston, Texas, United States, 77030
      • UT Health Science Center at Houston
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours Mary Immaculate Hospital
    • Richmond, Virginia, United States, 23226
      • Bon Secours St. Mary's Hospital of Richmond, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Fibrates or statins
  2. 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:

  1. Systemic corticosteroids
  2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo BID	Drug: Placebo
Experimental: IDN-6556; 25 mg BID of IDN-6556	Drug: IDN-6556; 25 mg BID; Other Names: emricasan; PF-03491390

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Conatus Pharmaceuticals Inc.
• Investigators: Study Chair: Dave Hagerty, MD, Conatus Pharmaceuticals

Publications and helpful links

General Publications

• Frenette CT, Morelli G, Shiffman ML, Frederick RT, Rubin RA, Fallon MB, Cheng JT, Cave M, Khaderi SA, Massoud O, Pyrsopoulos N, Park JS, Robinson JM, Yamashita M, Spada AP, Chan JL, Hagerty DT. Emricasan Improves Liver Function in Patients With Cirrhosis and High Model for End-Stage Liver Disease Scores Compared With Placebo. Clin Gastroenterol Hepatol. 2019 Mar;17(4):774-783.e4. doi: 10.1016/j.cgh.2018.06.012. Epub 2018 Jun 18.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: August 28, 2014
• First Submitted That Met QC Criteria: August 28, 2014
• First Posted (Estimate): September 3, 2014

Study Record Updates

• Last Update Posted (Actual): July 5, 2017
• Last Update Submitted That Met QC Criteria: June 6, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Liver Cirrhosis; Hepatic Cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: IDN-6556-10