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

NCT ID: NCT00597909

Last Updated: 2024-12-17

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-12-31
• Study Completion Date: 2008-09-30

Brief Summary

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).

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

Conditions

Hepatic Encephalopathy

Keywords

Ammonul®; sodium phenylacetate and sodium benzoate; hepatic encephalopathy; Grade 3 or 4 Hepatic Encephalopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1

Group Type: EXPERIMENTAL

sodium phenylacetate and sodium benzoate injection 10% / 10%

Intervention Type: DRUG

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)

Arm 2

Group Type: EXPERIMENTAL

sodium phenylacetate and sodium benzoate injection 10% / 10%

Intervention Type: DRUG

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)

Arm 3

Group Type: PLACEBO_COMPARATOR

placebo solution (10% dextrose)

Intervention Type: DRUG

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)

Interventions

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)

Intervention Type: 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)

Intervention Type: 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)

Intervention Type: DRUG

Other Intervention Names

Ammonul®; Ammonul®

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

UCSF-Fresno University

Fresno, California, United States

Loma Linda University Medical Center

Loma Linda, California, United States

Permian Research Foundation

Odessa, Texas, United States

Countries

United States

Related Links

http://www.nlm.nih.gov/medlineplus/braindiseases.html

Medline Plus: Brain Diseases

http://www.nlm.nih.gov/medlineplus/cirrhosis.html

Medline Plus: Cirrhosis

http://www.nlm.nih.gov/medlineplus/hepatitis.html

Medline Plus: Hepatitis

http://www.nlm.nih.gov/medlineplus/liverdiseases.html

Medline Plus: Liver Diseases

http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html

Medline Plus: Metabolic Disorders

http://www.clinicaltrials.gov/ct2/info/fdalinks

U.S. FDA Resources

Other Identifiers

HYP1203-004

Identifier Type: -

Identifier Source: org_study_id