Efficacy and Safety Study of Ammonul® in Patients With Grade 3 or 4 Hepatic Encephalopathy
Primary Purpose
Hepatic Encephalopathy
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
sodium phenylacetate and sodium benzoate injection 10% / 10%
sodium phenylacetate and sodium benzoate injection 10% / 10%
placebo solution (10% dextrose)
Sponsored by
About this trial
This is an interventional treatment trial for Hepatic Encephalopathy focused on measuring Ammonul®, sodium phenylacetate and sodium benzoate, hepatic encephalopathy, Grade 3 or 4 Hepatic Encephalopathy
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
Sites / Locations
- UCSF-Fresno University
- Loma Linda University Medical Center
- Permian Research Foundation
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Placebo Comparator
Arm Label
Arm 1
Arm 2
Arm 3
Arm Description
Outcomes
Primary Outcome Measures
Efficacy, as Assessed by Time to Grade 2 or Less in the West Haven Criteria Sustaining for 4 Hours or Longer
Secondary Outcome Measures
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
Full Information
NCT ID
NCT00597909
First Posted
January 9, 2008
Last Updated
March 1, 2016
Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland
1. Study Identification
Unique Protocol Identification Number
NCT00597909
Brief Title
Efficacy and Safety Study of Ammonul® in Patients With Grade 3 or 4 Hepatic Encephalopathy
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 Type
Interventional
2. Study Status
Record Verification Date
March 2016
Overall Recruitment Status
Terminated
Why Stopped
Study was terminated due to lack of enrollment and business decisions.
Study Start Date
December 2007 (undefined)
Primary Completion Date
September 2008 (Actual)
Study Completion Date
September 2008 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Horizon Pharma Ireland, Ltd., Dublin Ireland
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Encephalopathy
Keywords
Ammonul®, sodium phenylacetate and sodium benzoate, hepatic encephalopathy, Grade 3 or 4 Hepatic Encephalopathy
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm 1
Arm Type
Experimental
Arm Title
Arm 2
Arm Type
Experimental
Arm Title
Arm 3
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
sodium phenylacetate and sodium benzoate injection 10% / 10%
Other Intervention Name(s)
Ammonul®
Intervention Description
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
Intervention Name(s)
sodium phenylacetate and sodium benzoate injection 10% / 10%
Other Intervention Name(s)
Ammonul®
Intervention Description
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
Intervention Name(s)
placebo solution (10% dextrose)
Intervention Description
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)
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
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
Title
Efficacy, as Assessed by Proportion of Assessments With 1-grade Improvement, Using West Haven Criteria
Time Frame
96 hours of treatment and follow-up
Title
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
Title
Efficacy, as Assessed by Percentage of Subjects With a 1 or 2 Grade Improvement, Using the West Haven Criteria
Time Frame
participants will be followed for the duration of hospital stay, an expected average of 96 hours
Title
Efficacy, as Assessed by Severity of Hepatic Encephalopathy Using the Glasgow Coma Scale
Time Frame
96 hours of treatment and follow-up
Title
Effects of Ammonul® on Blood Ammonia Levels, Amino Acids and Carnitine
Time Frame
96 hours of treatment and follow-up
Title
Pharmacokinetic Characteristics of Ammonul® and Its Metabolites
Time Frame
Every 24 hours during treatment period of 96 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bruce Scharschmidt, MD
Organizational Affiliation
Horizon Pharma plc
Official's Role
Study Director
Facility Information:
Facility Name
UCSF-Fresno University
City
Fresno
State/Province
California
ZIP/Postal Code
93721
Country
United States
Facility Name
Loma Linda University Medical Center
City
Loma Linda
State/Province
California
ZIP/Postal Code
92354
Country
United States
Facility Name
Permian Research Foundation
City
Odessa
State/Province
Texas
ZIP/Postal Code
79761
Country
United States
12. IPD Sharing Statement
Links:
URL
http://www.nlm.nih.gov/medlineplus/braindiseases.html
Description
Medline Plus: Brain Diseases
URL
http://www.nlm.nih.gov/medlineplus/cirrhosis.html
Description
Medline Plus: Cirrhosis
URL
http://www.nlm.nih.gov/medlineplus/hepatitis.html
Description
Medline Plus: Hepatitis
URL
http://www.nlm.nih.gov/medlineplus/liverdiseases.html
Description
Medline Plus: Liver Diseases
URL
http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html
Description
Medline Plus: Metabolic Disorders
URL
http://www.clinicaltrials.gov/ct2/info/fdalinks
Description
U.S. FDA Resources
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Efficacy and Safety Study of Ammonul® in Patients With Grade 3 or 4 Hepatic Encephalopathy
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