Clinical trial NCT00004467: Randomized Study of Acetylcysteine in Patients With Acute Liver Failure Not Caused by Acetaminophen
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Liver Failure
Keywords: acute liver failure
gastrointestinal disorders
rare disease
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: University of Texas Southwestern Medical Center
First posted: 1999-10-19
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall survival rate
timeFrame: 3 weeks
Secondary outcomes:
measure: Survival without liver transplantation (Spontaneous Survival
timeFrame: 3 weeks
measure: Transplant rate
timeFrame: 3 weeks
measure: Length of hospital stay
timeFrame: 3 weeks
measure: Number of organ systems showing failure
timeFrame: 3 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Sacramento
country: United States
facility: University of California Davis
state: California
city: San Diego
country: United States
facility: University of California San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Chicago
country: United States
facility: Northwestern University Medical School
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health Systems
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: New York
country: United States
facility: Mount Sinai Medical Center, NY
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
Study officials:
affiliation: University of Texas Southwestern Medical Center at Dallas, Dallas, TX
name: William M. Lee, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.