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

Acute Liver Failure Clinical Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00004467
• Other study ID #: 199/13925 DK52827 (completed)
• Secondary ID: R03DK052827UTSMC
• Status: Completed
• Phase: Phase 3
• First received: October 18, 1999
• Last updated: October 11, 2017
• Start date: June 1998
• Est. completion date: November 2006

Study information

• Verified date: October 2017
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00587366

Recruitment information / eligibility

• Status: Completed
• Enrollment: 173
• Est. completion date: November 2006
• Est. primary completion date: November 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Liver Failure
• Liver Failure
• Liver Failure, Acute

Intervention

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.
• Placebo
Infusion of 5% dextrose

Locations

Country	Name	City	State
United States	University of Michigan Health Systems	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University Medical School	Chicago	Illinois
United States	Baylor University Medical Center	Dallas	Texas
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Mayo Clinic	Jacksonville	Florida
United States	University of California Los Angeles	Los Angeles	California
United States	Mount Sinai Medical Center, NY	New York	New York
United States	New York Presbyterian Hospital	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health Sciences University	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California Davis	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of California San Diego	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Mayo Clinic	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	University of Texas Southwestern Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival rate		3 weeks
Secondary	Survival without liver transplantation (Spontaneous Survival		3 weeks
Secondary	Transplant rate		3 weeks
Secondary	Length of hospital stay		3 weeks
Secondary	Number of organ systems showing failure		3 weeks

External Links

•   Acute Liver Failure Study Group