Efficacy and Safety Study of Ammonul® in Patients With Grade 3 or 4 Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a reversible neuropsychiatric syndrome seen in patients with
liver disease. The pathogenesis of HE is incompletely understood, but several pieces of
evidence identify ammonia as a key factor in the development of HE. The liver normally
detoxifies ammonia produced in the gastrointestinal tract. However, in patients with
cirrhosis, portosystemic shunting allows ammonia to bypass the liver and reach the systemic
circulation and the brain. The accumulation of ammonia in the brain, through mechanisms not
yet fully defined, lead to changes of consciousness, intellectual function, and behavior.

Ammonul is currently approved as adjuvant therapy for the management of hyperammonemia and
associated encephalopathy in patients with deficiencies in the enzymes of the urea cycle.
Ammonul removes nitrogenous ammonia in these patients through pathways alternative to the
urea cycle. It is anticipated that in patients with HE, Ammonul may lead to the scavenging
of ammonia through these alternative biochemical pathways taking place in tissues other than
the liver.

This study is designed to test the efficacy and safety of IV Ammonul® as a treatment for
acute episodes of elevated ammonia in patients with Grade 3 or 4 HE. Study was terminated
due to lack of enrollment and business decisions.

Inclusion Criteria:

- Male or female between the ages of 18 and 75 years

- Signed written informed consent by subject's representative

- Current diagnosis of chronic liver disease with cirrhosis

- West Haven score of Grade 3 or 4 Hepatic Encephalopathy

- Weight between 45 and 150 kg

- Elevated venous ammonia concentration, defined as a value above the normal range at
the local laboratory

- Estimated creatinine clearance of > 30 mL/min/1.73m², calculated using the
Cockcroft-Gault formula, or serum creatinine < 2.5 mg/dL [Cockcroft-Gault formula:
creatinine clearance = (140 - age) x weight in kg divided by (72 x serum creatinine
in mg/dL); multiply result by 0.85 for females]

- Adequate urinary output of ≥ 30 mL/hour for the last 2 hours if estimated creatinine
clearance is < 50 mL/min/1.73 m²

- Negative pregnancy test or documented sterilization procedure (tubal ligation or
hysterectomy) or 5 years post-menopausal

Exclusion Criteria:

- Major gastrointestinal bleeding (hematemesis, melena, or hematochezia) requiring
blood transfusion within the last 24 hours

- Uncontrolled sepsis, as defined by hemodynamic instability requiring vasopressor
agents (renal-dosed dopamine allowed)

- Current diagnosis of acute hepatic failure

- Alcohol ingestion during last 24 hours

- Post liver transplant

- Serum sodium < 120 mEq/L

- Serum potassium ≤ 3.5 mEq/L

- Use of probenecid, valproate, penicillin or its derivatives, or corticosteroids (oral
or IV) within the last 24 hours

- Use of any sedatives, benzodiazepines, or any neuro- or psycho-active drugs in the
last 6 hours and a positive urinary drug screen

- Subjects who received any mind-altering agents (such as barbiturates, propofol,
opioids, or benzodiazepines) to assist with intubation are not eligible while the
effects of the drug are still apparent

- Congestive heart failure (New York Heart Association Class III or IV)

- Seizures, dementia, or any neurologic or psychiatric condition within the last 72
hours that may interfere with the assessment of the mental state

- Current diagnosis of major aspiration pneumonia or pulmonary edema accompanied by an
oxygen saturation of ≤ 90% while breathing supplemental oxygen

- Laboratory test abnormalities determined to be clinically significant by the
investigator

- Enrollment in another experimental (interventional) protocol within the last 30 days
or 5 half-lives of the experimental drug, whichever s longer

- Any medical condition, which in the opinion of the investigator would constitute a
contraindication to enrollment in the study