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

• Sponsor: University of Texas Southwestern Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00896025
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 255
• Locations: 21
• Arms: 2
• Duration (Months): 87
• Patients Per Site: 12.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Liver Failure; Fulminant Hepatic Failure	Drug: N-acetylcysteine	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 255 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open label-comparator is historical data.Open label-comparator is historical data.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-Center Trial to Study Acute Liver Failure: N-Acetylcysteine (NAC) Open Label Use Study
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Oct 15, 2015
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Survival Rate With or Without Transplant [3 Weeks]

   The primary outcome is to compare all patients who survive (with or without transplant) to those who die.

2. Survival Rate With or Without Transplant [1-year follow-up]

   The primary outcome is to compare all patients who survive (with or without transplant) to those who die.

3. Survival Rate With or Without Transplant [2-year follow-up]

   The primary outcome is to compare all patients who survive (with or without transplant) to those who die.

Secondary Outcome Measures

1. 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). [3 Week follow-up]

   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.

2. 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). [1-year follow-up]

   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.

3. 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). [2-year follow-up]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	University of California, Los Angeles	Los Angeles	California	United States	90095
3	University of California, Davis	Sacramento	California	United States	95817
4	University of California, San Francisco	San Francisco	California	United States	94143
5	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32216
6	Northwestern University Medical School	Chicago	Illinois	United States	60611
7	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
8	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
9	Mayo Clinic, Rochester	Rochester	Minnesota	United States	55905
10	University of Nebraska	Omaha	Nebraska	United States	68198
11	Mount Sinai School of Medicine	New York	New York	United States	10029
12	New York Presbyterian Hospital (Columbia and Cornel)	New York	New York	United States	10032
13	Oregon Health Sciences University	Portland	Oregon	United States	97239
14	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
15	Albert Einstein Medical Center	Philadelphia	Pennsylvania	United States	19141
16	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
17	Medical University of South Carolina	Charleston	South Carolina	United States	29425
18	Baylor University Medical Center	Dallas	Texas	United States	75246
19	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
20	Virginia Commonwealth University	Richmond	Virginia	United States	23298
21	University of Washington	Seattle	Washington	United States	98195

Sponsors and Collaborators

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

Investigators

• Principal Investigator: William M Lee, MD, UT Southwestern Medical Center at Dallas

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Acute Liver Failure Website

Publications

None provided.

• Responsible Party: University of Texas Southwestern Medical Center
• ClinicalTrials.gov Identifier: NCT00896025
• Other Study ID Numbers: STU 012009-011; NIDDK U-01 058369
• First Posted: May 11, 2009
• Last Update Posted: Jun 1, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Texas Southwestern Medical Center: Liver disease
• Additional relevant MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Failure, Acute; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Arm/Group Title	N-acetycylcysteine
Arm/Group Description	Acute liver failure population
Period Title: Overall Study
STARTED	8
COMPLETED	8
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	N-acetycylcysteine
Arm/Group Description	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 NAC infusion for a total of 72 hours.
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 100%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46
Sex: Female, Male (Count of Participants)
Female	5 62.5%
Male	3 37.5%
Region of Enrollment (participants) [Number]
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Survival Rate With or Without Transplant
Description	The primary outcome is to compare all patients who survive (with or without transplant) to those who die.
Time Frame	3 Weeks

Outcome Measure Data

Analysis Population Description

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 there was no data to analyze.

Arm/Group Title	N-acetycylcysteine
Arm/Group Description	Acute liver failure population 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
Measure Participants	0

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	N-acetycylcysteine
Arm/Group Description	Acute liver failure population 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
Measure Participants	0

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	N-acetycylcysteine
Arm/Group Description	Acute liver failure population 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
Measure Participants	0

4. Secondary Outcome

Title	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).
Description	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.
Time Frame	3 Week follow-up

Outcome Measure Data

Analysis Population Description

Data was not collected since study was terminated, therefore there was no data to analyze.

Arm/Group Title	N-acetycylcysteine	Standard of Care
Arm/Group Description	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. 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	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.
Measure Participants	0	0

5. Secondary Outcome

Title	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).
Description	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.
Time Frame	1-year follow-up

Outcome Measure Data

Analysis Population Description

Data was not collected since study was terminated, therefore there was no data to analyze.

Arm/Group Title	N-acetycylcysteine	Standard of Care
Arm/Group Description	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. 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	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.
Measure Participants	0	0

6. Secondary Outcome

Title	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).
Description	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.
Time Frame	2-year follow-up

Outcome Measure Data

Analysis Population Description

Data was not collected since study was terminated, therefore there was no data to analyze.

Arm/Group Title	N-acetycylcysteine	Standard of Care
Arm/Group Description	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. 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	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.
Measure Participants	0	0

Adverse Events

Time Frame	Adverse events were collected during the 72-hour infusion period.
Arm/Group Title	N-acetycylcysteine
Arm/Group Description	Acute liver failure population 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
All Cause Mortality
	N-acetycylcysteine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	N-acetycylcysteine
	Affected / at Risk (%)	# Events
Total	0/8 (0%)
Other (Not Including Serious) Adverse Events
	N-acetycylcysteine
	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)
Skin and subcutaneous tissue disorders
Pruritus	1/8 (12.5%)	1

Limitations/Caveats

Early termination lead to zero subjects analyzed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.