Clinical Trial to Evaluation the Safety and Efficacy of GR-MD-02 for the Treatment of Liver Fibrosis and Resultant Portal Hypertension in Patients With Nash Cirrhosis

Exclusion Criteria

• •1. Has a history of hepatic decompensation including any episode of variceal bleeding, ascites not controlled by medication, or overt hepatic encephalopathy (defined by the clinical judgment of the principal investigator but shall include the presence of lethargy, disorientation, inappropriate behavior, and the presence of asterixis).
• •2. Has a presence of medium or large varices or varices with red signs regardless of size based on endoscopy.
• •* Small varices are defined by veins that occupy \<25% of the distal one third of the esophageal lumen when insufflated. Veins that completely flatten upon insufflation of the esophagus are not conserved varices. Any varices larger than that are medium (up to 50%) or large (\>50%).
• •* Red signs include red wale markings (dilated venules oriented longitudinally on the variceal surface), cherry red spots (small, red, spotty dilated venules usually approximately 2 mm in diameter on the variceal surface) or hematocystic spots (large, round, crimson red projection \>3 mm that look like a blood blister on the variceal surface).
• •3. Has had a prior transjugular porto systemic shunt procedure.
• •4. Has evidence of other forms of chronic liver disease including viral hepatitis B or C, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alpha 1 antitrypsin deficiency, alcoholic hepatitis, hemochromatosis, liver cancer, history of biliary diversion, or autoimmune hepatitis.
• •5. Has any of the following laboratory values:
• •* Serum alanine aminotransferase levels \>10 × the upper limits of normal
• •* Serum aspartate aminotransferase levels \>10 × the upper limits of normal
• •* Platelet count \<60 000/mm3
• •\*. Serum albumin ≤2.8 g/dL
• •* International normalized ratio (INR) ≥1.7
• •* Direct bilirubin ≥2.0 mg/dL
• •* Alpha fetoprotein \>200 ng/mL
• •6. Has a Model End-Stage Liver Disease (MELD) score ≥15 or Child Turcotte Pugh Class B or C.
• •7. Has an estimated creatinine clearance of \<50 mL/minute. Glomerular filtration rate will be estimated using the Cockcroft-Gault equation (Cockcroft 1976):
• •* Males: CrCl (mL/min) = (\[140 - age\] × weight) / (SCr × 72)
• •* Females: CrCl (mL/min) = (\[140 - age\]) × weight) / (SCr × 72)\] × 0.85
• •* Where CrCl is creatinine clearance, age is in years, weight is in kg, and SCr is serum creatinine in mg/dL
• •8. Is unwilling or unable to safely undergo HVPG or liver biopsy.
• •9. Has known positivity for human immunodeficiency virus (HIV) infection or a positive HIV test result at screening.
• •10. Has had major surgery within 8 weeks of randomization, significant traumatic injury within 6 months, or anticipation of need for major surgical procedure during the course of the study.
• •11. Has a history of a solid organ transplant requiring current immunosuppression therapy.
• •12. Has used nonselective β adrenergic inhibitors within 6 weeks prior to randomization.
• •13. Has planned or anticipated variceal ligation therapy during the study.
• •14. Has had weight reduction surgery within the past 3 years or plans to undergo weight reduction surgery during the study.
• •15. Has current, significant alcohol consumption or a history of significant alcohol consumption for a period of more than 3 consecutive months any time within 1 year prior to screening.
• •• Significant alcohol consumption is defined as more than 20 grams per day in females and more than 30 grams per day in males. On average, a standard drink in the United States is considered to be 14 grams of alcohol, equivalent to 12 fluid ounces of regular beer (5% alcohol), 5 fluid ounces of table wine (12% alcohol), or 1.5 fluid ounces of 80 proof spirits (40% alcohol).
• •A score of ≥8 on the Alcohol Use Disorders Identification Test (AUDIT) (Babor 2000) will result in exclusion.
• •16. Has a positive urine screen result for amphetamines, cocaine, or nonprescription opiates (heroin, morphine) at screening.
• •17. Has clinically significant and uncontrolled cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction within 6 months prior to randomization, unstable angina), New York Heart Association Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring devise/ablation or Grade II or greater peripheral vascular disease within 12 months prior to randomization.
• •18. Has a history of clinically significant hematologic, renal, hepatic, pulmonary, neurological, psychiatric, gastrointestinal, systemic inflammatory, metabolic or endocrine disorder or any other condition that, in the opinion of the investigator, renders the subject a poor candidate for inclusion into the study.
• •19. Has concurrent infection including diagnoses of fever of unknown origin at the time of randomization.
• •20. Has a history of malignancy, except for the following: adequately treated nonmetastatic basal cell skin cancer; any other type of skin cancer, except melanoma, that has been adequately treated and has not recurred for at least 1 year prior to enrollment; and adequately treated in situ cervical cancer that has not recurred for at least 1 year prior to screening.
• •21. Participates in an investigational new drug study within 30 days prior to randomization (including follow up visits) or at any time during the current study.
• •22. Has a clinically significant medical or psychiatric condition considered high risk for participation in an investigational study.
• •23. Fails to give informed consent.
• •24. Has known allergies to the IMP or any of its excipients.
• •25. Has previously received GR-MD-02 within 6 months of randomization.
• •26. Is an employee or family member of the investigator or study center personnel.