A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV (POLT-HCV-SVR)

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

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.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90095
      • UCLA Pfleger Liver Institute
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
    • Washington, District of Columbia, United States, 21287
      • Johns Hopkins Sibley Memorial Hospital
  • 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, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Clinic
    • New Orleans, Louisiana, United States, 70112
      • Tulane Health Science Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henery Ford Health System
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Physicians Company
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Milton Hershey Hospital
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Baylor All Saints Medical Center
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • Houston, Texas, United States, 77030
      • Liver Associates of Texas, PA
    • Houston, Texas, United States, 77030
      • VAMC/Baylor College of Medicine
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours Mary Immaculate Hospital
    • Richmond, Virginia, United States, 23249
      • McGuire DVAMC
    • Richmond, Virginia, United States, 23226
      • Bon Secours St. Mary's Hospital of Richmond
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington Harborview Medical Center

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
• 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

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; Placebo control
Experimental: IDN-6556; IDN-6556 25 mg BID	Drug: IDN-6556; Other Names: emricasan; PF-03491390

What is the study measuring?

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): February 15, 2018
• Study Completion (Actual): March 9, 2018

Study Registration Dates

• First Submitted: May 12, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (Estimate): May 14, 2014

Study Record Updates

• Last Update Posted (Actual): December 11, 2019
• Last Update Submitted That Met QC Criteria: November 21, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: liver fibrosis; hepatic fibrosis; hepatitis C; liver transplant; liver cirrhosis; hepatic cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis
• Other Study ID Numbers: IDN-6556-07