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

Sponsor

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

Overall Status

Completed

CT.gov ID

NCT00004467

Collaborator

University of Texas Southwestern Medical Center (Other)

173

Enrollment

Locations

Arms

101

Duration (Months)

6.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

OBJECTIVES:

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Liver Failure	Drug: N-acetylcysteine (NAC) Drug: Placebo	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

173 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Study Start Date :

Jun 1, 1998

Actual Primary Completion Date :

Nov 1, 2006

Actual Study Completion Date :

Nov 1, 2006

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Overall survival rate [3 weeks]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Patients less than age 18 or over 70 years of age.
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.
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.
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.
ALF thought secondary to intrahepatic malignancy. Patients with hepatic malignancy experiencing ALF have 100% mortality and are not transplant candidates.
Patients who exhibit signs of cerebral herniation at the time of enrollment.
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-0005
2	Mayo Clinic	Scottsdale	Arizona	United States	85259
3	University of California Los Angeles	Los Angeles	California	United States	90024
4	University of California Davis	Sacramento	California	United States	95817
5	University of California San Diego	San Diego	California	United States	92103-0707
6	University of California San Francisco	San Francisco	California	United States	94115
7	Mayo Clinic	Jacksonville	Florida	United States	32216
8	Northwestern University Medical School	Chicago	Illinois	United States	60611
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	University of Michigan Health Systems	Ann Arbor	Michigan	United States	48109
11	Mayo Clinic	Rochester	Minnesota	United States	55905
12	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
13	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3330
14	Mount Sinai Medical Center, NY	New York	New York	United States	10029
15	New York Presbyterian Hospital	New York	New York	United States	10032-3784
16	Duke University Medical Center	Durham	North Carolina	United States	27715
17	Oregon Health Sciences University	Portland	Oregon	United States	97201-3098
18	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
19	Albert Einstein Medical Center	Philadelphia	Pennsylvania	United States	19141
20	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
21	Medical University of South Carolina	Charleston	South Carolina	United States	29425
22	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75235-8897
23	Baylor University Medical Center	Dallas	Texas	United States	75246
24	Virginia Commonwealth University	Richmond	Virginia	United States	23298-0341
25	University of Washington Medical Center	Seattle	Washington	United States	98195-6043