Safety and Efficacy of AST-120 Compared to Lactulose in Patients With Hepatic Encephalopathy (AST015)

• Efficacy: Change in Hepatic Encephalopathy Scoring Algorithm (HESA) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Efficacy: Reduction of venous ammonia levels [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Efficacy: Serum bile acids and amino acid profile [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Efficacy: Reduction in itching (visual analog scale) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Efficacy: Presence or absence of asterixis [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Safety: Clinical laboratory tests [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
• Safety: Physical examination, vital signs (blood pressure, heart rate, respiration rate, body temperature) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]

• Efficacy: Change in Hepatic Encephalopathy Scoring Algorithm (HESA) [ Time Frame: 4 weeks ]
• Efficacy: Reduction of venous ammonia levels [ Time Frame: 4 weeks ]
• Efficacy: Serum bile acids and amino acid profile [ Time Frame: 4 weeks ]
• Efficacy: Reduction in itching (visual analog scale) [ Time Frame: 4 weeks ]
• Efficacy: Presence or absence of asterixis [ Time Frame: 4 weeks ]
• Safety: Clinical laboratory tests [ Time Frame: 4 weeks ]
• Safety: Physical examination, vital signs (blood pressure, heart rate, respiration rate, body temperature) [ Time Frame: 4 weeks ]

The purpose of this study is to evaluate the safety and effectiveness of the experimental drug AST-120 compared to lactulose in patients with mild hepatic encephalopathy.

This is a multi-center, open-label, four week trial comparing AST-120 to lactulose in patients with mild (Stage 1-2) hepatic encephalopathy.

Patients will be randomized into two groups:

• Lactulose
• AST-120

Patients meeting the inclusion criteria will take either AST-120 or lactulose for 4 weeks (28 days). AST-120 will be distributed in 2 gram sachets to be taken four times daily. Lactulose will be taken in the same formulation, at the same dose and frequency as previously prescribed for the individual patient.

Lactulose naïve patients who are randomized to lactulose will receive an initial dose of 30cc twice a day. The dose should be titrated at the discretion of the investigator until the patient is experiencing 2-3 soft stools per day.

Patients randomized to AST-120 will receive 2 grams four times a day for the duration of the study. Titration of AST-120 will NOT be allowed.

Patients will be evaluated throughout the study for efficacy and safety. A follow-up visit will be scheduled 1 week after the end of the 4 week treatment period.

• Drug: AST-120
  AST-120
• Drug: lactulose
  lactulose
  Other Name: Chronulac, Constilac, Constulose, Duphalac, Evalose

• Active Comparator: 1
  Intervention: Drug: lactulose
• Experimental: 2
  Intervention: Drug: AST-120

Inclusion Criteria:

• Patients with End Stage Liver Disease secondary to any cause (patients who have undergone portosystemic shunting (TIPS) procedure > 3 months prior to randomization can be included)
• Lactulose naïve patients or patients currently on an established dose of lactulose
• MELD score ≤ 15 (MELD score up to 20 is allowable if it has remained stable for at least 3 months)
• Meet the criteria for Stage 1-2 hepatic encephalopathy according to the Westhaven Scale
• Patients must have discontinued rifaximin or other oral antibiotics for at least 48 hours prior to randomization
• Able and willing to comply with all protocol procedures for the planned duration of the study
• Able and willing to understand, sign and date an informed consent document, and authorize access to protected health information
• Have a person (spouse, relative, or friend) willing to accompany the patient to the study visits (patients in this condition are not recommended to drive a vehicle)
• Females must be postmenopausal, surgically incapable of bearing children, or practicing a reliable method of birth control (intrauterine devices, spermicide and barrier). Partner/spouse sterility may also qualify at the investigator's discretion. Females of child-bearing potential must have a negative urine pregnancy test at baseline.

Note: Patients already on lactulose and randomized to AST-120 will stop taking lactulose on the day they begin taking AST-120.

Exclusion Criteria:

• Patients whose condition necessitates continuous administration of antibiotics (e.g. rifaximin, neomycin, metronidazole)
• Patients undergoing chemotherapy for treatment of cancer (patients with hepatocellular carcinoma being treated by methods other than chemotherapy may be enrolled)
• Patients who require continued treatment with narcotics or sedatives
• Patients who have active GI bleeding
• Patients who have an active infection
• Patients who have signs and symptoms of severe dehydration
• Poor tolerability of venipuncture or lack of adequate venous access for required blood sampling
• Unable to attend all visits required by the protocol
• Female patients must be EXCLUDED if they are pregnant, breast feeding, planning to become pregnant during the study or using hormonal contraception as their only method of birth control