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

Phase 2

Completed

Conditions: Hepatic Cirrhosis
Portal Hypertension
Liver Cirrhosis

Interventions: Drug: IDN-6556

Registration Number: NCT02230683

Lead Sponsor: Conatus Pharmaceuticals Inc.

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IDN-6556 - Overall population	IDN-6556	Overall evaluable population treated with IDN-6556 25 mg twice daily
IDN-6556 - Subgroup with Baseline HVPG < 12 mmHg	IDN-6556	Subgroup for patients with Baseline HVPG \< 12 mmHg that have been treated with IDN-6556 25 mg twice daily
IDN-6556 - Subgroup Baseline HVPG ≥ 12 mmHg	IDN-6556	Subgroup for patients with Baseline HVPG ≥ 12 mmHg that have been treated with IDN-6556 25 mg twice daily

Primary Outcome Measures

Name	Time	Method
Hepatic Venous Pressure Gradient (HVPG)	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
cCK18/M30	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
Change in cCK18/M30	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

Name	Time	Method
Change in Alanine Aminotransferase (ALT)	Baseline to 28 days/EOT	Median change of ALT from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Change in Aspartate Aminotransferase (AST)	Baseline to 28 days/EOT	Median change of AST from Baseline to Day 28/EOT (end of treatment) for IDN-6556
Concentration of Caspase 3/7 RLU	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

Trial Locations

Locations (16): University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
North Shore University Hospital
🇺🇸
Manhasset, New York, United States
St. Luke's Health Baylor College of Medicine
🇺🇸
Houston, Texas, United States
University of Utah Hospital
🇺🇸
Salt Lake City, Utah, United States
University of Texas Health Science Center at Houston
🇺🇸
Houston, Texas, United States
Bon Secours Mary Immaculate Hospital
🇺🇸
Newport News, Virginia, United States
VA Connecticut Healthcare System
🇺🇸
West Haven, Connecticut, United States
Johns Hopkins Sibley Memorial Hospital
🇺🇸
Washington, District of Columbia, United States
Rutgers New Jersey Medical School
🇺🇸
Newark, New Jersey, United States
Johns Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
New York University Lagone Medical Center
🇺🇸
NYC, New York, United States
Albert Einstein Medical Center
🇺🇸
Philadelphia, Pennsylvania, United States
University of Miami
🇺🇸
Miami, Florida, United States
University of Pennsylvania
🇺🇸
Philadelphia, Pennsylvania, United States
Bon Secours St. Mary's Hospital
🇺🇸
Richmond, Virginia, United States
McGuire DVAMC
🇺🇸
Richmond, Virginia, United States