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

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

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).

Study Overview

• Status: Terminated
• Conditions: Hepatic Encephalopathy
• Intervention / Treatment: Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; Drug: placebo solution (10% dextrose)

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. Study was terminated due to lack of enrollment and business decisions.

Study with completed results acquired from Horizon in 2024

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Fresno, California, United States, 93721
      • UCSF-Fresno University
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
  • Texas
    • Odessa, Texas, United States, 79761
      • Permian Research Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1	Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; 5.5 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours); Other Names: Ammonul®; Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; 2.75 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours); Other Names: Ammonul®
Experimental: Arm 2	Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; 5.5 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours); Other Names: Ammonul®; Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%; 2.75 g/m² diluted in 10% dextrose, IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours); Other Names: Ammonul®
Placebo Comparator: Arm 3	Drug: placebo solution (10% dextrose); Placebo solution (10% dextrose), IV as a 2-hour loading (initial) dose, followed by the same dose over 24 hours (maintenance infusion); maintenance infusion will be continued for 3 days (70 hours)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Efficacy, as Assessed by Time to Grade 2 or Less in the West Haven Criteria Sustaining for 4 Hours or Longer	Time to Grade 2 or less sustaining for 4 hours or longer

Secondary Outcome Measures

Outcome Measure	Time Frame
Safety, as Assessed by Reported Adverse Events, Clinical Laboratory Measurements, Changes in Vital Signs, and Changes in 12-lead ECG Results	96 hours of treatment and follow-up
Efficacy, as Assessed by Proportion of Assessments With a 2-grade Improvement, Using West Haven Criteria	96 hours of treatment and follow-up
Efficacy, as Assessed by Proportion of Assessments With 1-grade Improvement, Using West Haven Criteria	96 hours of treatment and follow-up
Efficacy, as Assessed by Time Spent in an Improved State by 1 or 2 Grades Using the West Haven Criteria	96 hours of treatment and follow-up
Efficacy, as Assessed by Percentage of Subjects With a 1 or 2 Grade Improvement, Using the West Haven Criteria	participants will be followed for the duration of hospital stay, an expected average of 96 hours
Efficacy, as Assessed by Severity of Hepatic Encephalopathy Using the Glasgow Coma Scale	96 hours of treatment and follow-up
Effects of Ammonul® on Blood Ammonia Levels, Amino Acids and Carnitine	96 hours of treatment and follow-up
Pharmacokinetic Characteristics of Ammonul® and Its Metabolites	Every 24 hours during treatment period of 96 hours

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• U.S. FDA Resources
• Medline Plus: Brain Diseases
• Medline Plus: Cirrhosis
• Medline Plus: Hepatitis
• Medline Plus: Liver Diseases
• Medline Plus: Metabolic Disorders

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): September 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: January 9, 2008
• First Submitted That Met QC Criteria: January 17, 2008
• First Posted (Estimated): January 18, 2008

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: November 25, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: hepatic encephalopathy; Ammonul®; sodium phenylacetate and sodium benzoate; Grade 3 or 4 Hepatic Encephalopathy
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Digestive System Diseases; Liver Diseases; Brain Diseases, Metabolic; Liver Failure; Hepatic Insufficiency; Brain Diseases; Hepatic Encephalopathy; Anti-Infective Agents; Antineoplastic Agents; Antifungal Agents; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Sodium Benzoate; Phenylacetic acid
• Other Study ID Numbers: HYP1203-004