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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Hepatic Encephalopathy

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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%<br>* 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)<br>* Other names: Ammonul®;|
| Experimental: Arm 2<br> | Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%<br>* 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)<br>* Other names: Ammonul®;|
| Placebo Comparator: Arm 3<br> | Drug: placebo solution (10% dextrose)<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ammonul®, sodium phenylacetate and sodium benzoate, hepatic encephalopathy, Grade 3 or 4 Hepatic Encephalopathy