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

Sponsor:	Hyperion Therapeutics, Inc.
Information provided by:	Hyperion Therapeutics, Inc.
ClinicalTrials.gov Identifier:	NCT00597909

Purpose

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).

Condition	Intervention	Phase
Hepatic Encephalopathy	Drug: sodium phenylacetate and sodium benzoate injection 10% / 10% Drug: placebo solution (10% dextrose)	Phase II

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

Resource links provided by NLM:

Drug Information available for: Dextrose Phenylacetic acid Sodium phenylacetate Phenyl acetate Sodium benzoate Potassium benzoate

U.S. FDA Resources

Further study details as provided by Hyperion Therapeutics, Inc.:

Primary Outcome Measures:

Efficacy, as assessed by time to Grade 2 or less in the West Haven criteria sustaining for 4 hours or longer [ Time Frame: Time to Grade 2 or less sustaining for 4 hours or longer ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Safety, as assessed by reported adverse events, clinical laboratory measurements, changes in vital signs, and changes in 12-lead ECG results [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Efficacy, as assessed by proportion of assessments with a 2-grade improvement, using West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Efficacy, as assessed by proportion of assessments with 1-grade improvement, using West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Efficacy, as assessed by time spent in an improved state by 1 or 2 grades using the West Haven criteria [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Efficacy, as assessed by percentage of subjects with a 1 or 2 grade improvement, using the West Haven criteria [ Time Frame: At any time point and at each specific time point ] [ Designated as safety issue: No ]
Efficacy, as assessed by severity of hepatic encephalopathy using the Glasgow Coma Scale [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Effects of Ammonul® on blood ammonia levels, amino acids and carnitine [ Time Frame: 96 hours of treatment and follow-up ] [ Designated as safety issue: No ]
Pharmacokinetic characteristics of Ammonul® and its metabolites [ Time Frame: Every 24 hours during treatment period of 96 hours ] [ Designated as safety issue: No ]

Estimated Enrollment:	105
Study Start Date:	December 2007
Study Completion Date:	September 2008
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 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 Name: Ammonul®
Experimental: 2	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 Name: Ammonul®
Placebo Comparator: 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)

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.

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00597909

Locations

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

Sponsors and Collaborators

Hyperion Therapeutics, Inc.

Investigators

Study Director:

Bruce Scharschmidt, MD

Hyperion Therapeutics, Inc.

More Information

Additional Information:

Genetics Home Reference: Liver Diseases This link exits the ClinicalTrials.gov site

Genetics Home Reference: Metabolic Disorders This link exits the ClinicalTrials.gov site

Medline Plus: Brain Diseases This link exits the ClinicalTrials.gov site

Medline Plus: Cirrhosis This link exits the ClinicalTrials.gov site

Medline Plus: Hepatitis This link exits the ClinicalTrials.gov site

Medline Plus: Liver Diseases This link exits the ClinicalTrials.gov site

Medline Plus: Metabolic Disorders This link exits the ClinicalTrials.gov site

U.S. FDA Resources This link exits the ClinicalTrials.gov site

ChemIDplus: sodium phenylacetate This link exits the ClinicalTrials.gov site

ChemIDplus: sodium benzoate This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Bruce Scharschmidt, MD, Senior Vice President and Chief Medical Officer, Hyperion Therapeutics, Inc.
ClinicalTrials.gov Identifier:	NCT00597909 History of Changes
Other Study ID Numbers:	HYP1203-004
Study First Received:	January 9, 2008
Last Updated:	April 27, 2011
Health Authority:	United States: Food and Drug Administration

Keywords provided by Hyperion Therapeutics, Inc.:

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

Additional relevant MeSH terms:

Hepatic Encephalopathy
Brain Damage, Chronic
Delirium
Encephalitis
Neurotoxicity Syndromes
Liver Failure
Hepatic Insufficiency
Liver Diseases
Digestive System Diseases
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolic Diseases
Confusion

Neurobehavioral Manifestations
Neurologic Manifestations
Signs and Symptoms
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Central Nervous System Viral Diseases
Virus Diseases
Central Nervous System Infections
Poisoning
Substance-Related Disorders
Benzoates
Sodium Benzoate
Phenylacetic acid
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on February 09, 2012