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

Primary Purpose

Liver Fibrosis, Hepatic Fibrosis, Liver Cirrhosis

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
IDN-6556
Placebo
Sponsored by
Conatus Pharmaceuticals Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Liver Fibrosis focused on measuring liver transplant, hepatitis C, liver fibrosis, hepatic fibrosis, liver cirrhosis, hepatic cirrhosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Southern California Research Center
  • Scripps Clinic
  • Loma Linda University Medical Center
  • UCLA Pfleger Liver Institute
  • Georgetown University Hospital
  • Johns Hopkins Sibley Memorial Hospital
  • University of Florida
  • University of Miami
  • Piedmont Atlanta Hospital
  • Rush University Medical Center
  • University of Chicago Medicine
  • Indiana University
  • University of Kansas Medical Center
  • University of Louisville
  • Tulane Health Science Center
  • Ochsner Clinic
  • John Hopkins Hospital
  • Beth Israel Deaconess Medical Center
  • Henery Ford Health System
  • Saint Louis University
  • Rutgers New Jersey Medical School
  • Columbia University Medical Center
  • University of Cincinnati Physicians Company
  • University of Pennsylvania Milton Hershey Hospital
  • Temple University Hospital
  • Albert Einstein Medical Center
  • Baylor All Saints Medical Center
  • Liver Associates of Texas, PA
  • University of Texas Health Science Center at Houston
  • VAMC/Baylor College of Medicine
  • University of Utah
  • Bon Secours Mary Immaculate Hospital
  • Bon Secours St. Mary's Hospital of Richmond
  • McGuire DVAMC
  • University of Washington Harborview Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IDN-6556

Placebo

Arm Description

IDN-6556 25 mg BID

Placebo BID

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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
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
Alanine Aminotransferase (ALT) - Change From Baseline
Liver function laboratory parameter
Aspartate Aminotransferase (AST) Change From Baseline
Liver function laboratory parameter
Caspase 3/7 Change From Baseline
Mechanistic biomarker of liver function
cCK18/M30 Change From Baseline
Mechanistic biomarker of liver function.
flCK18/M65 Change From Baseline
Mechanistic biomarker of liver function
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)
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
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
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

Full Information

First Posted
May 12, 2014
Last Updated
November 21, 2019
Sponsor
Conatus Pharmaceuticals Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02138253
Brief Title
A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV
Acronym
POLT-HCV-SVR
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
May 2014 (undefined)
Primary Completion Date
February 15, 2018 (Actual)
Study Completion Date
March 9, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Conatus Pharmaceuticals Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Fibrosis, Hepatic Fibrosis, Liver Cirrhosis, Hepatic Cirrhosis
Keywords
liver transplant, hepatitis C, liver fibrosis, hepatic fibrosis, liver cirrhosis, hepatic cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
64 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IDN-6556
Arm Type
Experimental
Arm Description
IDN-6556 25 mg BID
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo BID
Intervention Type
Drug
Intervention Name(s)
IDN-6556
Other Intervention Name(s)
emricasan, PF-03491390
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo control
Primary Outcome Measure Information:
Title
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score
Description
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.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score (Observed Cases Only)
Description
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
Time Frame
24 months
Title
Number of Participants With At Least a One Stage Reduction From Baseline in Ishak Fibrosis Score
Description
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
Time Frame
12 months
Title
Alanine Aminotransferase (ALT) - Change From Baseline
Description
Liver function laboratory parameter
Time Frame
Baseline and 24 months
Title
Aspartate Aminotransferase (AST) Change From Baseline
Description
Liver function laboratory parameter
Time Frame
Baseline and 24 months
Title
Caspase 3/7 Change From Baseline
Description
Mechanistic biomarker of liver function
Time Frame
Baseline and 24 months
Title
cCK18/M30 Change From Baseline
Description
Mechanistic biomarker of liver function.
Time Frame
Baseline and 24 months
Title
flCK18/M65 Change From Baseline
Description
Mechanistic biomarker of liver function
Time Frame
Baseline and 24 months
Title
Ishak Modification of Knodell Histological Activity Index - Interface Hepatitis
Description
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)
Time Frame
24 months
Title
Ishak Modification of Knodell Histological Index - Confluent Necrosis
Description
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
Time Frame
24 months
Title
Ishak Modification of Knodell Histological Index - Parenchymal Injury
Description
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
Time Frame
24 months
Title
Ishak Modification of Knodell Histological Index - Portal Inflammation
Description
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
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Hagerty, MD
Organizational Affiliation
Conatus Pharmaceuticals
Official's Role
Study Chair
Facility Information:
Facility Name
Southern California Research Center
City
Coronado
State/Province
California
ZIP/Postal Code
92118
Country
United States
Facility Name
Scripps Clinic
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Facility Name
Loma Linda University Medical Center
City
Loma Linda
State/Province
California
ZIP/Postal Code
92354
Country
United States
Facility Name
UCLA Pfleger Liver Institute
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
Johns Hopkins Sibley Memorial Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
21287
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Piedmont Atlanta Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
University of Chicago Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Indiana University
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Kansas Medical Center
City
Kansas City
State/Province
Kansas
ZIP/Postal Code
66160
Country
United States
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Facility Name
Tulane Health Science Center
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Ochsner Clinic
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
John Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Henery Ford Health System
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Saint Louis University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63104
Country
United States
Facility Name
Rutgers New Jersey Medical School
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07103
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Cincinnati Physicians Company
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Facility Name
University of Pennsylvania Milton Hershey Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Temple University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Albert Einstein Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19141
Country
United States
Facility Name
Baylor All Saints Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Liver Associates of Texas, PA
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas Health Science Center at Houston
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
VAMC/Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Bon Secours Mary Immaculate Hospital
City
Newport News
State/Province
Virginia
ZIP/Postal Code
23602
Country
United States
Facility Name
Bon Secours St. Mary's Hospital of Richmond
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23226
Country
United States
Facility Name
McGuire DVAMC
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Facility Name
University of Washington Harborview Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Learn more about this trial

A Trial of IDN-6556 in Post Orthotopic Liver Transplant for Chronic HCV

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