Non-Alcoholic Steatohepatitis (NASH) Cirrhosis and Severe Portal Hypertension MedDRA version: 20.1 Level: PT Classification code 10036200 Term: Portal hypertension System Organ Class: 10019805 - Hepatobiliary disorders MedDRA version: 22.0 Level: PT Classification code 10053219 Term: Non-alcoholic steatohepatitis System Organ Class: 10
Conditions
Sponsors
Conatus Pharmaceuticals Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female subjects 18 years or older, able to provide written informed consent and able to understand and willing to comply with the requirements of the study. 2. Cirrhosis due to NASH with exclusion of other causes of cirrhosis (e.g. chronic viral hepatitis, alcoholic liver disease, etc.) Diagnosis of cirrhosis is based on: - Biopsy OR - Clinical evidence: platelet count ALT, and either nodular liver surface on imaging or splenomegaly NASH is based on at least 1 of the following: - Prior or current biopsy showing some but not all diagnostic features of NASH (e.g. only fat or ballooning degeneration or inflammation) but with no evidence for viral hepatitis or other liver disease AND either fatty liver disease on prior imaging or at least 1 metabolic risk factor (as above) for at least 5 years preceding the diagnosis of cirrhosis Note: Previous viral hepatitis that was curatively treated (with sustained viral response) is not an exclusion as long as: 1) viral eradication was achieved at least 3 years prior to the diagnosis of cirrhosis and 2) all other criteria are met for NASH as the etiology of cirrhosis 3. Compensated cirrhosis (no history of or presence of clinically evident ascites, variceal hemorrhage, or encephalopathy, and on no medications to treat these complications) OR Decompensated cirrhosis with no more than 1 prior significant decompensating event: a. If prior decompensating event was variceal hemorrhage, event must have occurred at least 3 months prior to Day 1 b. If prior decompensating event was ascites requiring chronic diuretics, ascites should be well controlled (not clinically evident, i.e. no ascites or ascites only detectable by ultrasound examination) on a stable dose of diuretics for at least 3 months prior to Day 1 c. If prior decompensating event was hepatic encephalopathy = grade II or requiring hospitalization, encephalopathy should be well-controlled (Stage 0 or 1) on stable medication for at least 3 months prior to Day 1 Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently stable without clinically evident ascites or encephalopathy and on no medications for these conditions does not count as a prior significant decompensating event 4. Severe portal hypertension defined as HVPG =12 mmHg (see Section 8.4.1 for recommendations to identify subjects more likely to meet the HVPG criteria) 5. Subjects who are on NSBB, nitrates, diuretics, lactulose, rifaximin, or statins must be on a stable dose for at least 3 months prior to Day 1 6.Willingness to utilize effective contraception (for both males and females of reproductive potential) from Screening to 4 weeks after the last dose of study drug 7. Platelet count =125 k/mm3 or transient elastography = 20 kPa during screening 8. If on therapeutic dose of vitamin E, stable for 6 months prior to Day 1. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 192 F.1.3 Elderly (
Exclusion criteria
Exclusion criteria: 1. Evidence of severe decompensation, defined as: a. Presence or history of more than one type of significant decompensating event (clinically evident ascites requiring chronic diuretics, variceal hemorrhage, and/or overt encephalopathy) Note: Previous transient ascites or hepatic encephalopathy in a subject who is currently stable without clinically evident ascites or encephalopathy and on no medications for these conditions does not count towards this exclusion (see Inclusion Criteria #4). b. One type of decompensating event with the following characteristics: - More than 1 episode of variceal hemorrhage or bleeding from a portal hypertensive source (e.g. portal hypertensive gastropathy) - Ascites that has required more than 1 large-volume paracentesis (>5 L) for treatment or that has been complicated by spontaneous bacterial peritonitis, hyponatremia (serum Na 3 times upper limit of normal (ULN) or AST >5 times ULN during screening 4. Estimated creatinine clearance 50 ng/mL 10. History or presence of clinically concerning cardiac arrhythmias, or prolongation of screening (pre-treatment) QTcF interval of >500 msec 11. History of or active malignancies, other than those successfully treated with curative intent and believed to be cured 12. Significant systemic or major illness other than liver disease that in the opinion of the investigator would preclude the subject from participating in and completing the study, including but not limited to acute coronary syndrome or stroke within 6 months of screening or major surgery within 3 months of screening 13. Prior liver transplant 14. Change in diabetes medications within 3 months of screening, including initiation, discontinuation, or change in dose except for medications titrated according to blood glucose 15. Uncontrolled diabetes mellitus (HbA1c >9%) within 3 months of screening 16. Restrictive bariatric surgery or bariatric device within 1 year of screening or prior malabsorptive bariatric surgery 17. Known human immunodeficiency virus infection 18. Use of controlled substances (including inhaled or injected drugs) or non-prescribed use of prescription drugs within 1 year of screening to the point of interfering with the s
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess whether emricasan compared to placebo leads to a mean decrease in hepatic venous pressure gradient (HVPG) at Week 24 in subjects with NASH cirrhosis and severe portal hypertension. ; Secondary Objective: - To assess the safety and tolerability of emricasan - To evaluate the dose response of emricasan on portal pressure as assessed by HVPG at week 24 - To assess whether emricasan compared to placebo improves HVPG response using a 20% reduction from baseline response deifinition at week 24 - To assess whether emricasan compared to placebo decreases mechanism specific (caspase 3/7) and non-specific (ALT) biomarkers at weeks 24 and 48 ;Primary end point(s): Mean Change from Baseline at Week 25 in Hepatic Venous Pressure Gradient (HVPG);Timepoint(s) of evaluation of this end point: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The change from baseline at Weeks 24 and 48 in Caspase 3/7 and ALT measurements and HVPG response (20% reduction from baseline) at Week 24. ;Timepoint(s) of evaluation of this end point: Per protocol | — |
Countries
France, Germany, Spain, Switzerland, United States
Contacts
Public ContactClinical Trial Information
Conatus Pharmaceuticals Inc.
Outcome results
None listed