Study of N-Acetylcysteine in Acute Liver Failure (ALF) (ONAC)

A Multi-Center Trial to Study Acute Liver Failure: N-Acetylcysteine (NAC) Open Label Use Study

This proposed study is a multi-center open label study to determine if N-acetylcysteine has any survival benefits in patients with acute liver failure.

Study Overview

• Status: Terminated
• Conditions: Acute Liver Failure; Fulminant Hepatic Failure
• Intervention / Treatment: Drug: N-acetylcysteine

Detailed Description

Patients admitted to study sites with carefully defined criteria for acute liver failure and who are thought not to have acetaminophen toxicity, mushroom poisoning, pregnancy-related liver failure, or malignancy will be eligible. Each patient will receive intravenously in solution of 5% dextrose in water containing N-acetylcysteine, beginning at a dose of 150 mg/kg bodyweight in 250 ml 5% dextrose over one hour, and in declining doses over a total of 72 hours. Care of patients and consideration of transplantation or other clinical decisions will not be affected by the study or the use of study drug.

• Study Type: Interventional
• Enrollment (Actual): 255
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Sacramento, California, United States, 95817
      • University of California, Davis
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Mayo Clinic, Jacksonville
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Medical School
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic, Rochester
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital (Columbia and Cornel)
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written Informed consent from patient's next of kin
• Altered mentation of any degree (encephalopathy)
• Evidence of moderately severe clotting abnormalities (international normalized ratio ≥ 1.5)
• A presumed acute illness onset of less than 26 weeks
• Admitted to study site hospital intensive care units with acute liver failure and who can be evaluated and started on treatment within the first 24 hours of hospitalization
• All subjects will be between 18 and 70 years
• The NIH guidelines on the inclusion of women and minorities as subjects will be observed

Exclusion Criteria:

• Patients less than age 18 or over 70 years of age
• Acetaminophen or mushroom poisoning induced liver failure
• Patients with a diagnosis of shock liver (ischemic hepatopathy)
• Acute liver failure of pregnancy
• Acute liver failure thought secondary to intra-hepatic malignancy
• Cerebral herniation
• Intractable arterial hypotension
• Severe sepsis (temperature >39º C and/or significant bacteremia) present at the time of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: N-acetycylcysteine; Each eligible Acute Liver Failure patient will be given N-acetylcysteine (NAC), beginning at a dose of 150 mg/kg bodyweight in 250 ml 5% dextrose over one hour, followed by 50 mg/kg in 500 ml 5% dextrose over four hours, and 125 mg/kg in 1000 ml 5% dextrose over 19 hours, then 150 mg/kg in 1000 ml 5% dextrose per 24 hours for an additional 48 hours. The patient will be on continuous N-acetylcysteine infusion for a total of 72 hours.	Drug: N-acetylcysteine; Patients will be included in the trial from the onset of any hepatic coma grade and will receive NAC for the following 72 hrs. NAC Solutions: The N-acetylcysteine will be added to 5% dextrose in defined concentrations according to the sequence of four specific doses required for the study. i.Solution A: 150 mg/kg bodyweight in 250 ml 5% dextrose over one hour ii.Solution B: 50 mg/kg in 500 ml 5% dextrose over four hours iii.Solution C: 125 mg/kg in 1000 ml 5% dextrose over 19 hours iv.Solution D: 150 mg/kg in 1000 ml 5% dextrose per 24 hours v.Solution E: 150 mg/kg in 1000 ml 5% dextrose per 24 hours; Other Names: Mucomyst
NO_INTERVENTION: Standard of care; Each eligible Acute Liver Failure patient for whom the investigator chooses not to utilize N-acetylcysteine may serve as a control and receives standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival Rate With or Without Transplant	The primary outcome is to compare all patients who survive (with or without transplant) to those who die.	3 Weeks
Survival Rate With or Without Transplant	The primary outcome is to compare all patients who survive (with or without transplant) to those who die.	1-year follow-up
Survival Rate With or Without Transplant	The primary outcome is to compare all patients who survive (with or without transplant) to those who die.	2-year follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Compare Patients Who Survive Without Transplantation to All Other Patients Enrolled in This Study (Those Who Receive a Transplant and Live, Those Who Receive a Transplant and Die, or Those Who Die Before Transplantation).	The estimated minimum enrollment for any statistical validity was 100 patients. Due to low enrollment (8 participants) and the likelihood of generating any meaningful study data moving forward, the DSMB recommended the early termination of the study. Data was not collected since study was terminated, therefore no data to analyze.	3 Week follow-up
To Compare Patients Who Survive Without Transplantation to All Other Patients Enrolled in This Study (Those Who Receive a Transplant and Live, Those Who Receive a Transplant and Die, or Those Who Die Before Transplantation).	The estimated minimum enrollment for any statistical validity was 100 patients. Due to low enrollment (8 participants) and the likelihood of generating any meaningful study data moving forward, the DSMB recommended the early termination of the study. Data was not collected since study was terminated.	1-year follow-up
To Compare Patients Who Survive Without Transplantation to All Other Patients Enrolled in This Study (Those Who Receive a Transplant and Live, Those Who Receive a Transplant and Die, or Those Who Die Before Transplantation).	The estimated minimum enrollment for any statistical validity was 100 patients. Due to low enrollment (8 participants) and the likelihood of generating any meaningful study data moving forward, the DSMB recommended the early termination of the study. Data was not collected since study was terminated.	2-year follow-up

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: William M Lee, MD, UT Southwestern Medical Center at Dallas

Publications and helpful links

Helpful Links

• Acute Liver Failure Website

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (ACTUAL): October 15, 2015
• Study Completion (ACTUAL): March 1, 2016

Study Registration Dates

• First Submitted: May 8, 2009
• First Submitted That Met QC Criteria: May 8, 2009
• First Posted (ESTIMATE): May 11, 2009

Study Record Updates

• Last Update Posted (ACTUAL): June 1, 2020
• Last Update Submitted That Met QC Criteria: May 29, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Liver disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: STU 012009-011; NIDDK U-01 058369

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO