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

• ClinicalTrials.gov Identifier: NCT02230683
• Recruitment Status: Completed
• First Posted: September 3, 2014
• Results First Posted: December 21, 2016
• Last Update Posted: December 21, 2016
• Sponsor: Conatus Pharmaceuticals Inc.
• Information provided by (Responsible Party): Conatus Pharmaceuticals Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Liver Cirrhosis; Hepatic Cirrhosis; Portal Hypertension	Drug: IDN-6556	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Pilot Trial to Evaluate the Safety, Tolerability and Efficacy of IDN-6556 in Cirrhotic Subjects With Portal Hypertension
• Study Start Date: August 2014
• Actual Primary Completion Date: May 2015
• Actual Study Completion Date: June 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Hepatic Venous Pressure Gradient (HVPG) [ Time Frame: Baseline to Day 28/EOT (end of treatment) ]
   Mean change of HVPG [mmHg] from Baseline to Day 28/EOT (end of treatment) for IDN-6556
2. cCK18/M30 [ Time Frame: Change from Baseline to Day 28/EOT ]
   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
3. Change in cCK18/M30 [ Time Frame: Baseline to Day 28/EOT (end of treatment) ]
   Median change of caspase-cleaved cytokeratin serum levels (cCK18/M30) from Baseline to Day 28/EOT (end of treatment) for IDN-6556

Secondary Outcome Measures :

1. Change in Alanine Aminotransferase (ALT) [ Time Frame: Baseline to 28 days/EOT ]
   Median change of ALT from Baseline to Day 28/EOT (end of treatment) for IDN-6556
2. Change in Aspartate Aminotransferase (AST) [ Time Frame: Baseline to 28 days/EOT ]
   Median change of AST from Baseline to Day 28/EOT (end of treatment) for IDN-6556
3. Concentration of Caspase 3/7 RLU [ Time Frame: Baseline to 28 days/EOT ]
   Median change of concentration of Caspase 3/7 Relative Light Units from Baseline to Day 28/EOT (end of treatment) for IDN-6556

Eligibility Criteria

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

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
• 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.

Contacts and Locations

Locations

United States, Connecticut

VA Connecticut Healthcare System

West Haven, Connecticut, United States, 06516

United States, District of Columbia

Johns Hopkins Sibley Memorial Hospital

Washington, District of Columbia, United States, 20016

United States, Florida

University of Miami

Miami, Florida, United States, 33136

United States, Maryland

Johns Hopkins Hospital

Baltimore, Maryland, United States, 21287

United States, Mississippi

University of Mississippi Medical Center

Jackson, Mississippi, United States, 39216

United States, New Jersey

Rutgers New Jersey Medical School

Newark, New Jersey, United States, 07103

United States, New York

North Shore University Hospital

Manhasset, New York, United States, 11030

New York University Lagone Medical Center

NYC, New York, United States, 10016

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

Albert Einstein Medical Center

Philadelphia, Pennsylvania, United States, 19141

United States, Texas

St. Luke's Health Baylor College of Medicine

Houston, Texas, United States, 77030

University of Texas Health Science Center at Houston

Houston, Texas, United States, 77030

United States, Utah

University of Utah Hospital

Salt Lake City, Utah, United States, 84132

United States, Virginia

Bon Secours Mary Immaculate Hospital

Newport News, Virginia, United States, 23602

Bon Secours St. Mary's Hospital

Richmond, Virginia, United States, 23226

McGuire DVAMC

Richmond, Virginia, United States, 23249

Sponsors and Collaborators

Conatus Pharmaceuticals Inc.

Investigators

• Study Chair: David Hagerty, MD; Conatus Pharmaceuticals

More Information

• Responsible Party: Conatus Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT02230683
• Other Study ID Numbers: IDN-6556-11
• First Posted: September 3, 2014
• Results First Posted: December 21, 2016
• Last Update Posted: December 21, 2016
• Last Verified: October 2016

Keywords provided by Conatus Pharmaceuticals Inc.:

Liver Cirrhosis; Hepatic Cirrhosis; Portal Hypertension

Additional relevant MeSH terms:

Liver Cirrhosis; Hypertension, Portal; Hypertension; Fibrosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Liver Diseases; Digestive System Diseases