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

NCT00597909 | Terminated Phase 2 Results DMC

• 1 other identifier: HYP1203-004
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 3

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).

Conditions

Hepatic Encephalopathy

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• 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

Study Arms (3)

Arm 1

EXPERIMENTAL

Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%

Arm 2

EXPERIMENTAL

Drug: sodium phenylacetate and sodium benzoate injection 10% / 10%

Arm 3

PLACEBO COMPARATOR

Drug: placebo solution (10% dextrose)

Interventions

sodium phenylacetate and sodium benzoate injection 10% / 10% 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)

Also known as: Ammonul®

Arm 1

placebo solution (10% dextrose) 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)

Arm 3

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Amgen: lead

Study Sites (3)

UCSF-Fresno University

Fresno, California, 93721, United States

Location

Loma Linda University Medical Center

Loma Linda, California, 92354, United States

Location

Permian Research Foundation

Odessa, Texas, 79761, United States

Location

Related Links

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

MeSH Terms

Conditions

Hepatic Encephalopathy; Lymphoma, Follicular

Interventions

phenylacetic acid; Sodium Benzoate; ammonul; Glucose

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzoic Acid; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Hexoses; Monosaccharides; Sugars; Carbohydrates

Limitations and Caveats

One participant was enrolled but did not receive drug or was randomized.

Results Point of Contact

• Title: Bruce Scharschmidt, MD
• Organization: Horizon Pharma plc

bscharschmidt@horizonpharma.com

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2008
• First Posted: January 18, 2008
• Study Start: December 1, 2007
• Primary Completion: September 1, 2008
• Study Completion: September 1, 2008
• Last Updated: December 17, 2024
• Results First Posted: March 31, 2016

Record last verified: 2024-11

Locations

US (3)