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N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00248625
Recruitment Status : Completed
First Posted : November 4, 2005
Results First Posted : July 28, 2016
Last Update Posted : July 28, 2016
Sponsor:
Collaborator:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Robert Squires, Jr., University of Pittsburgh

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Conditions Acute Liver Failure
Hepatic Encephalopathy
Interventions Drug: N-acetylcysteine
Drug: Placebo
Enrollment 184
Recruitment Details Participants were from an established registry of children with acute liver failure. Entry criteria: children <18 years, absence of a known chronic liver disease, biochemical evidence of acute liver injury, and a liver-based coagulopathy. Evidence of hepatic encephalopathy was required if the prothrombin time (PT) was between 15-19.9 seconds
Pre-assignment Details  
Arm/Group Title Placebo N-acetylcysteine (NAC)
Hide Arm/Group Description

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to placebo consisting of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, liver transplantation, or death within 7 days of randomization.

Dextrose in water: Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) and water. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, LTx, or death within 7 days of randomization.

N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge.

Period Title: Overall Study
Started 92 92
Completed 92 90
Not Completed 0 2
Reason Not Completed
Withdrawal by Subject             0             2
Arm/Group Title N-acetylcysteine (NAC) Placebo Total
Hide Arm/Group Description Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Total of all reporting groups
Overall Number of Baseline Participants 92 92 184
Hide Baseline Analysis Population Description
All participants who were randomized were included in the baseline analysis.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 92 participants 92 participants 184 participants
<=18 years
92
 100.0%
92
 100.0%
184
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 92 participants 92 participants 184 participants
3.7
(0.8 to 10.5)
4.5
(1.0 to 9.5)
4.1
(0.9 to 10.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 92 participants 92 participants 184 participants
Female
45
  48.9%
38
  41.3%
83
  45.1%
Male
47
  51.1%
54
  58.7%
101
  54.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 92 participants 92 participants 184 participants
American Indian or Alaska Native
0
   0.0%
1
   1.1%
1
   0.5%
Asian
3
   3.3%
5
   5.4%
8
   4.3%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
15
  16.3%
15
  16.3%
30
  16.3%
White
68
  73.9%
65
  70.7%
133
  72.3%
More than one race
3
   3.3%
4
   4.3%
7
   3.8%
Unknown or Not Reported
3
   3.3%
2
   2.2%
5
   2.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 92 participants 92 participants 184 participants
Canada 2 3 5
United States 61 68 129
United Kingdom 29 21 50
Coma Grade of Hepatic Encephalopathy   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 92 participants 92 participants 184 participants
0-1 65 68 133
2-4 27 24 51
[1]
Measure Description: West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants > 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing.
1.Primary Outcome
Title Survival
Hide Description Spontaneous survival without transplant plus survival following transplantation
Time Frame One year following randomization
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who were enrolled in the study were included in the survival analysis
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: Participants
68 76
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.19
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
2.Secondary Outcome
Title Spontaneous Recovery
Hide Description Survival without liver transplantation
Time Frame One year following randomization
Hide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled in study
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: participants
33 49
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
3.Secondary Outcome
Title Cumulative Percent Incidence of Transplantation by 1 Year
Hide Description [Not Specified]
Time Frame Within 1 year of randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: percentage of participants
45 35
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.21
Comments [Not Specified]
Method Pepe and Mori test of CIF difference
Comments [Not Specified]
4.Secondary Outcome
Title Length of Hospital Stay
Hide Description [Not Specified]
Time Frame Randomization to hospital discharge
Hide Outcome Measure Data
Hide Analysis Population Description
All participants enrolled in study with hospital stay information, 2 participants (1 in each arm) did not have hospital discharge information.
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 91 91
Median (Inter-Quartile Range)
Unit of Measure: days
103
(13 to 103)
21
(9 to 103)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.053
Comments [Not Specified]
Method Kruskal-Wallis
Comments [Not Specified]
5.Secondary Outcome
Title Categorized Length of ICU Stay
Hide Description The length of ICU stay was categorized as number of days in ICU within 7 days of randomization, unless participant either died or received an LTx within this time period. Special categories were created for these cases.
Time Frame Within 7 days of randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: participants
0 days 29 34
1 day 3 4
2 days 3 4
3 days 2 0
4 days 1 3
5 days 4 3
6 days 5 3
7 days 9 14
underwent LTx w/i 7 days of randomization 28 22
died w/o LTx w/i 7 days of randomization 8 5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.29
Comments [Not Specified]
Method Cochran-Armitage trend
Comments [Not Specified]
6.Secondary Outcome
Title Number of Organ Systems Failing
Hide Description [Not Specified]
Time Frame Within 7 days of randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: participants
0 44 46
1 21 23
2 15 12
3 11 8
4 1 3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.74
Comments [Not Specified]
Method Cochran-Armitage trend
Comments [Not Specified]
7.Secondary Outcome
Title Highest Coma Grade of Hepatic Encephalopathy
Hide Description West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants > 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing.
Time Frame Within 7 days of randomization
Hide Outcome Measure Data
Hide Analysis Population Description
All enrolled participants where coma grade could be assessed. Four participants (two in each randomization arm) could not have coma grade assessed during the 7 days after randomization.
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 90 90
Measure Type: Number
Unit of Measure: participants
0 28 27
I 16 21
II 20 19
III 15 17
IV 11 6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments [Not Specified]
Method Cochran-Armitage tren
Comments [Not Specified]
8.Secondary Outcome
Title Infectious Complication
Hide Description [Not Specified]
Time Frame Within 7 days of randomization
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description:
Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study

Overall Number of Participants Analyzed 92 92
Measure Type: Number
Unit of Measure: Participants
20 21
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection N-acetylcysteine (NAC), Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.86
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame Seven day randomization treatment period
Adverse Event Reporting Description Regular investigator assessment
 
Arm/Group Title N-acetylcysteine (NAC) Placebo
Hide Arm/Group Description

Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days

N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge.

Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive

Dextrose in water: Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, LTx, or death within 7 days of randomization.

All-Cause Mortality
N-acetylcysteine (NAC) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
N-acetylcysteine (NAC) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   5/92 (5.43%)   4/92 (4.35%) 
Blood and lymphatic system disorders     
Aplastic Anemia   1/92 (1.09%)  0/92 (0.00%) 
Cardiac disorders     
Bradycardiac episode   1/92 (1.09%)  0/92 (0.00%) 
Bigeminy   0/92 (0.00%)  1/92 (1.09%) 
Ear and labyrinth disorders     
Hearing loss   0/92 (0.00%)  1/92 (1.09%) 
Endocrine disorders     
Hypoglycemia   1/92 (1.09%)  0/92 (0.00%) 
Gastrointestinal disorders     
Small intestine ulcerations   0/92 (0.00%)  1/92 (1.09%) 
General disorders     
Fever   0/92 (0.00%)  1/92 (1.09%) 
Infections and infestations     
Bacteremia   1/92 (1.09%)  0/92 (0.00%) 
Epstein-Barr virus   1/92 (1.09%)  0/92 (0.00%) 
Fever, chills, sinusitis   1/92 (1.09%)  0/92 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Respiratory distress   1/92 (1.09%)  0/92 (0.00%) 
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
N-acetylcysteine (NAC) Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   19/92 (20.65%)   16/92 (17.39%) 
Cardiac disorders     
Arrhythmia   1/92 (1.09%)  4/92 (4.35%) 
Bradycardia   1/92 (1.09%)  1/92 (1.09%) 
Eye disorders     
Dilated and fixed pupils   1/92 (1.09%)  0/92 (0.00%) 
General disorders     
Sleepiness   1/92 (1.09%)  1/92 (1.09%) 
High Fever   1/92 (1.09%)  1/92 (1.09%) 
Infections and infestations     
Infection   11/92 (11.96%)  8/92 (8.70%) 
Respiratory, thoracic and mediastinal disorders     
Bronchospasm   1/92 (1.09%)  0/92 (0.00%) 
Aspiration   1/92 (1.09%)  0/92 (0.00%) 
Pleural effusion   1/92 (1.09%)  0/92 (0.00%) 
Skin and subcutaneous tissue disorders     
Rash   4/92 (4.35%)  2/92 (2.17%) 
Vascular disorders     
Hypertension   1/92 (1.09%)  0/92 (0.00%) 
Indicates events were collected by systematic assessment
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Robert H. Squires, Jr.
Organization: University of Pittsburgh
Phone: 412-692-8648
EMail: squiresr@upmc.edu
Publications:
Layout table for additonal information
Responsible Party: Robert Squires, Jr., University of Pittsburgh
ClinicalTrials.gov Identifier: NCT00248625    
Other Study ID Numbers: IRB #: 0608007
U01DK072146 ( U.S. NIH Grant/Contract )
First Submitted: November 3, 2005
First Posted: November 4, 2005
Results First Submitted: February 19, 2016
Results First Posted: July 28, 2016
Last Update Posted: July 28, 2016