Randomized Study of Acetylcysteine in Patients With Acute Liver Failure Not Caused by Acetaminophen

OBJECTIVES:

I. Determine the safety and efficacy of a short course (72 hours) of intravenous acetylcysteine in patients with acute liver failure for whom no antidote or specific treatment is available.

Study Overview

• Status: Completed
• Conditions: Acute Liver Failure
• Intervention / Treatment: Drug: Placebo; Drug: N-acetylcysteine (NAC)

Detailed Description

PROTOCOL OUTLINE: This is a randomized, multicenter study. Patients are randomized to receive intravenous acetylcysteine or placebo for 72 hours. Treatment must begin within 12 hours of hospitalization. Patients who advance to grade III or IV encephalopathy are eligible for liver transplantation.

Patients are followed at 3 weeks.

• Study Type: Interventional
• Enrollment (Actual): 173
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294-0005
      • University of Alabama at Birmingham
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic
  • California
    • Los Angeles, California, United States, 90024
      • University of California Los Angeles
    • Sacramento, California, United States, 95817
      • University of California Davis
    • San Diego, California, United States, 92103-0707
      • University of California San Diego
    • San Francisco, California, United States, 94115
      • University of California San Francisco
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Mayo Clinic
  • 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 Health Systems
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198-3330
      • University of Nebraska Medical Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center, NY
    • New York, New York, United States, 10032-3784
      • New York Presbyterian Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27715
      • Duke University Medical Center
  • Oregon
    • Portland, Oregon, United States, 97201-3098
      • 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, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75235-8897
      • University of Texas Southwestern Medical Center at Dallas
  • Virginia
    • Richmond, Virginia, United States, 23298-0341
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195-6043
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

This is a phase III blinded study, which will involve approximately 200 patients. For this purpose, acute liver failure will be defined as onset of any mental status alteration and coagulopathy (INR > 1.5) within 26 weeks of onset of a hepatitic illness, with no evidence of underlying chronic liver disease. Eligible patients will be those 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 or those who evolve to altered mentation if already in the hospital. All subjects will be between 18 and 70 years. Patients transferred from referring hospitals to a study site may be considered for enrollment, provided that no other specific treatment protocol has begun, and that no liver support device (bioartificial liver (BAL), extracorporeal liver assist device (ELAD), transgenic pig perfusion) has been used or is contemplated. Use of fresh frozen plasma infusions will not disqualify patients from participation.

Exclusion Criteria

1. Patients less than age 18 or over 70 years of age.
2. ALF patients where acetaminophen or mushroom poisoning is assessed or Suspected to be a significant contributing or sole cause of the illness. Both these diagnoses require specific antidote therapy, including NAC in the case of acetaminophen, rather than randomized or non-specific treatment.
3. Patients with a diagnosis of shock liver (ischemic hepatopathy), since the overall outcome for these patients in largely determined by the underlying etiology of the condition leading to shock. Heat stroke is not excluded.
4. Acute liver failure of pregnancy or the HELLP syndrome (pregnancy associated hemolysis and coagulopathy). The effect of NAC on the fetus or the mother has not been determined; in addition, pregnancy-related liver diseases usually mandate rapid delivery of the infant.
5. ALF thought secondary to intrahepatic malignancy. Patients with hepatic malignancy experiencing ALF have 100% mortality and are not transplant candidates.
6. Patients who exhibit signs of cerebral herniation at the time of enrollment.
7. Patients who demonstrate the presence of intractable arterial hypotension (arterial systolic blood pressure equal to or below 70 mmHg) present, or require inotropic drugs at the time of enrollment.
8. Severe sepsis (temperature >39o C and/or significant bacteremia) present at the time of enrollment.

In general, acute liver failure (ALF) patients comprise somewhat more women than men, but there is no preponderance of any racial group, other than that expected on the basis of geographic differences. No exclusion will be made on the basis of race, ethnic group or gender. Criteria for inclusion of women and minorities will be those established in the NIH guidelines. Each study site will provide for review a log of patients considered for the NAC study with no identifiers, yielding only gender and age, race and reason for not participating as a check on gender or ethnic bias.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Infusion of 5% dextrose
Experimental: N-acetylcysteine (NAC)	Drug: N-acetylcysteine (NAC); Infusion of 5% dextrose with N-acetylcysteine with an initial loading dose of 150 mg/kg/h of NAC over 1 hour, followed by 12.5 mg/kg/h for 4 hours, then continuous infusions of 6.25 mg/kg/h for the remaining 67 hours.; Other Names: Acetadote

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival rate	3 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Survival without liver transplantation (Spontaneous Survival	3 weeks
Transplant rate	3 weeks
Length of hospital stay	3 weeks
Number of organ systems showing failure	3 weeks

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, Davern TJ 2nd, Murray NG, McCashland T, Reisch JS, Robuck PR; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009 Sep;137(3):856-64, 864.e1. doi: 10.1053/j.gastro.2009.06.006. Epub 2009 Jun 12. Erratum In: Gastroenterology. 2013 Sep;145(3):695. Dosage error in article text.
• Singh S, Hynan LS, Rule JA, Lee WM. Changes in alpha-foetoprotein and Gc-globulin in relation to outcomes in non-acetaminophen acute liver failure. Liver Int. 2019 Dec;39(12):2368-2373. doi: 10.1111/liv.14216. Epub 2019 Sep 10.

Helpful Links

• Acute Liver Failure Study Group

Study record dates

Study Major Dates

• Study Start: June 1, 1998
• Primary Completion (Actual): November 1, 2006
• Study Completion (Actual): November 1, 2006

Study Registration Dates

• First Submitted: October 18, 1999
• First Submitted That Met QC Criteria: October 18, 1999
• First Posted (Estimate): October 19, 1999

Study Record Updates

• Last Update Posted (Actual): October 13, 2017
• Last Update Submitted That Met QC Criteria: October 11, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: rare disease; acute liver failure; gastrointestinal disorders
• 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: 199/13925 DK52827 (completed); R03DK052827 (U.S. NIH Grant/Contract); UTSMC-IRB-0697-27200 (Other Identifier: University of Texas Southwest Medical Center); R01DK058369 (U.S. NIH Grant/Contract); U01DK058369 (NIH)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No