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

Information source: Horizon Pharma Ireland, Ltd., Dublin Ireland
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hepatic Encephalopathy

Intervention: sodium phenylacetate and sodium benzoate injection 10% / 10% (Drug); sodium phenylacetate and sodium benzoate injection 10% / 10% (Drug); placebo solution (10% dextrose) (Drug)

Phase: Phase 2

Status: Withdrawn

Sponsored by: Horizon Pharma Ireland, Ltd., Dublin Ireland

Official(s) and/or principal investigator(s):
Bruce Scharschmidt, MD, Study Director, Affiliation: Horizon Pharma Ireland, Ltd., Dublin Ireland


The primary purpose of this study is to evaluate the safety and effectiveness of Ammonul in subjects who become hospitalized with Grade 3 or 4 hepatic encephalopathy (HE).

Clinical Details

Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Two Doses of AMMONUL (Sodium Phenylacetate and Sodium Benzoate) Injection 10% / 10% in Subjects With Grade 3 or 4 Hepatic Encephalopathy

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Efficacy, as assessed by time to Grade 2 or less in the West Haven criteria sustaining for 4 hours or longer

Secondary outcome:

Safety, as assessed by reported adverse events, clinical laboratory measurements, changes in vital signs, and changes in 12-lead ECG results

Efficacy, as assessed by proportion of assessments with a 2-grade improvement, using West Haven criteria

Efficacy, as assessed by proportion of assessments with 1-grade improvement, using West Haven criteria

Efficacy, as assessed by time spent in an improved state by 1 or 2 grades using the West Haven criteria

Efficacy, as assessed by percentage of subjects with a 1 or 2 grade improvement, using the West Haven criteria

Efficacy, as assessed by severity of hepatic encephalopathy using the Glasgow Coma Scale

Effects of Ammonul® on blood ammonia levels, amino acids and carnitine

Pharmacokinetic characteristics of Ammonul® and its metabolites

Detailed description: 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.


Minimum age: 18 Years. Maximum age: 75 Years. Gender(s): Both.


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


- 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

Locations and Contacts

UCSF-Fresno University, Fresno, California 93721, United States

Loma Linda University Medical Center, Loma Linda, California 92354, United States

Permian Research Foundation, Odessa, Texas 79761, United States

Additional Information

Genetics Home Reference: Liver Diseases

Medline Plus: Brain Diseases

Medline Plus: Cirrhosis

Medline Plus: Hepatitis

Medline Plus: Liver Diseases

Medline Plus: Metabolic Disorders

U.S. FDA Resources

ChemIDplus: sodium phenylacetate

ChemIDplus: sodium benzoate

Starting date: December 2007
Last updated: April 27, 2011

Page last updated: August 20, 2015

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