Clinical trial NCT02230683: A Study of IDN-6556 in Cirrhotic Subjects With Portal Hypertension
Official title: An Open-Label Pilot Trial to Evaluate the Safety, Tolerability and Efficacy of IDN-6556 in Cirrhotic Subjects With Portal Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Cirrhosis
Hepatic Cirrhosis
Portal Hypertension
Keywords: Liver Cirrhosis
Hepatic Cirrhosis
Portal Hypertension
Lead sponsor: Conatus Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2014-09-03
Enrollment: 23
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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
* 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.

Primary outcomes:
measure: Hepatic Venous Pressure Gradient (HVPG)
timeFrame: Baseline to Day 28/EOT (end of treatment)
measure: cCK18/M30
timeFrame: Change from Baseline to Day 28/EOT
measure: Change in cCK18/M30
timeFrame: Baseline to Day 28/EOT (end of treatment)
Secondary outcomes:
measure: Change in Alanine Aminotransferase (ALT)
timeFrame: Baseline to 28 days/EOT
measure: Change in Aspartate Aminotransferase (AST)
timeFrame: Baseline to 28 days/EOT
measure: Concentration of Caspase 3/7 RLU
timeFrame: Baseline to 28 days/EOT
Other outcomes:
Locations:
city: West Haven
country: United States
facility: VA Connecticut Healthcare System
state: Connecticut
city: Washington
country: United States
facility: Johns Hopkins Sibley Memorial Hospital
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: NYC
country: United States
facility: New York University Lagone Medical Center
state: New York
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Houston
country: United States
facility: St. Luke's Health Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Newport News
country: United States
facility: Bon Secours Mary Immaculate Hospital
state: Virginia
city: Richmond
country: United States
facility: Bon Secours St. Mary's Hospital
state: Virginia
city: Richmond
country: United States
facility: McGuire DVAMC
state: Virginia
Study officials:
affiliation: Conatus Pharmaceuticals Inc.
name: David Hagerty, MD
role: STUDY_CHAIR
References: