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

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

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.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Johns Hopkins Sibley Memorial Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • 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
    • NYC, New York, United States, 10016
      • New York University Lagone Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • Houston, Texas, United States, 77030
      • St. Luke's Health Baylor College of Medicine
  • 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, 23249
      • McGuire DVAMC
    • Richmond, Virginia, United States, 23226
      • Bon Secours St. Mary's Hospital

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

• Evidence of portal hypertension as evidenced by any of the following:

  1. Splenomegaly, on imaging and/or clinical evaluation, with platelet count of <120,000 at study entry, or
  2. Presence of small sized varices on screening endoscopy and/or collateral circulation on imaging, or
  3. 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:

  1. Renal failure defined as creatinine ≥ 2.0 mg/dL
  2. Cerebral failure defined as hepatic encephalopathy grade III or IV
  3. Coagulation failure defined as INR ≥ 2.5 or platelets ≤ 20x109/L
  4. 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:

  1. β-blockers, including carvedilol
  2. Nitrates
  3. Vasopressin (or analogues)
  4. 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:

  1. Fibrates or statins
  2. Angiotensin II receptor antagonist or angiotensin converting enzyme (ACE) inhibitor

• Use of the following drugs within 2 months of Screening:

  1. Systemic corticosteroids
  2. Pentoxifylline
  3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): June 1, 2015

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 (Estimate): December 21, 2016
• Last Update Submitted That Met QC Criteria: October 28, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Liver Cirrhosis; Portal Hypertension; Hepatic Cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Liver Diseases; Fibrosis; Hypertension; Liver Cirrhosis; Hypertension, Portal
• Other Study ID Numbers: IDN-6556-11