N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT00248625
• Collaborator: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Enrollment: 184
• Locations: 20
• Arms: 2
• Duration (Months): 129
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

We have completed patient enrollment in the the double blind, randomized, placebo-controlled trial of intravenous (IV) N-acetylcysteine (NAC) vs. placebo for the treatment of non-acetaminophen ALF. The purpose of this study is to examine the safety and efficacy of intravenous NAC in children with ALF for whom no antidote or other specific treatment is available. Inclusion in the NAC Study required enrollment in the Pediatric Acute Liver Failure (PALF) Study Registry.

Condition or Disease	Intervention/Treatment	Phase
Acute Liver Failure; Hepatic Encephalopathy	Drug: N-acetylcysteine; Drug: Placebo	Phase 3

Detailed Description

The Pediatric Acute Liver Failure (PALF) Study Group to identify, characterize, and develop management strategies for infants, children and adolescents who present with acute liver failure. The PALF study group includes 20 sites (17 in the United States, 2 in the United Kingdom, and 1 in Canada). The primary objective of the Pediatric Acute Liver Failure (PALF) study is to collect, maintain, analyze, and report clinical, epidemiological, and outcome data in children with ALF, including information derived from biospecimens.

Patients enrolled in the PALF study registry were able to enroll in the NAC study providing they met the additional required inclusion/exclusion criteria.

Study Design

• Study Type: Interventional
• Actual Enrollment: 184 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multi-center Study of the Safety and Efficacy of N-acetylcysteine in the Treatment of Acute Liver Failure in Pediatric Patients Not Caused by Acetaminophen.
• Study Start Date: Jan 1, 2000
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: N-acetylcysteine (NAC) Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days	Drug: 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.; Other Names: Mucomyst
Placebo Comparator: placebo Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive	Drug: Placebo; Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (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. Treatment was stopped earlier than 7 days in the case of hospital discharge, liver transplantation, or death within 7 days of randomization.; Other Names: dextrose in water

Outcome Measures

Primary Outcome Measures

1. Survival [One year following randomization]

   Spontaneous survival without transplant plus survival following transplantation

Secondary Outcome Measures

1. Spontaneous Recovery [One year following randomization]

   Survival without liver transplantation

2. Cumulative Percent Incidence of Transplantation by 1 Year [Within 1 year of randomization]

3. Length of Hospital Stay [Randomization to hospital discharge]

4. Categorized Length of ICU Stay [Within 7 days of randomization]

   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.

5. Number of Organ Systems Failing [Within 7 days of randomization]

6. Highest Coma Grade of Hepatic Encephalopathy [Within 7 days of randomization]

   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.

7. Infectious Complication [Within 7 days of randomization]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Meet entry criteria for and be enrolled in the Pediatric Acute Liver Failure prospective database.

• Able to be evaluated and initiate treatment within the first 24 hours of hospitalization

• Patients transferred from referring hospitals to the study site may be considered for enrollment, provided that no other treatment protocol has begun, and that no liver support device (BAL, extracorporeal liver assist device, transgenic pig perfusion) has been used or is contemplated.

• Use of fresh frozen plasma infusions will not disqualify patients from participation.

Exclusion Criteria:

• older than 18 years of age

• pregnancy

• ALF that is secondary to acute acetaminophen toxicity, mushroom poisoning, or a known malignancy.

• Patients who exhibit signs of cerebral herniation, have intractable arterial hypotension, require inotropic drugs, or demonstrate signs of sepsis (temperature ≥ 39.5o C or bacteremia) at the time of enrollment

• No exclusion will be made on the basis of race, ethnic group or gender.

• Criteria for inclusion of females and minorities will be those established in the NIH guidelines

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	University of Colorado, Denver Children's Hospital	Denver	Colorado	United States	80218
3	Emory University, Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
4	Children's Memorial Hospital	Chicago	Illinois	United States	60614
5	Riley Children's Hospital	Indianapolis	Indiana	United States	46202
6	Johns Hopkins University	Baltimore	Maryland	United States	21287
7	Harvard University, Boston Children's Hospital	Boston	Massachusetts	United States	02115
8	University of Michigan	Ann Arbor	Michigan	United States	48109
9	St. Louis Children's Hospital	St. Louis	Missouri	United States	63110
10	Mount Sinai Hospital	New York	New York	United States	10029
11	Columbia-Presbyterian	New York	New York	United States	10032
12	University of Cincinnati, Cincinnati Children's Hospital	Cincinnati	Ohio	United States	45229
13	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
14	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
15	Children's Medical Center of Dallas	Dallas	Texas	United States	75235
16	Baylor College of Medicine	Houston	Texas	United States	77030
17	University of Washington	Seattle	Washington	United States	98105
18	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
19	Birmingham Children's Hospital	Birmingham		United Kingdom	B4 6NH
20	King's College Hospital (London, UK)	London		United Kingdom	SE59RS

Sponsors and Collaborators

• University of Pittsburgh
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Robert H Squires, M.D., Children's Hospital of Pittsburgh, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Publications

• Alonso EM. Acute liver failure in children: the role of defects in fatty acid oxidation. Hepatology. 2005 Apr;41(4):696-9. Review.
• James LP, Alonso EM, Hynan LS, Hinson JA, Davern TJ, Lee WM, Squires RH; Pediatric Acute Liver Failure Study Group. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics. 2006 Sep;118(3):e676-81.
• Narkewicz MR, Dell Olio D, Karpen SJ, Murray KF, Schwarz K, Yazigi N, Zhang S, Belle SH, Squires RH; Pediatric Acute Liver Failure Study Group. Pattern of diagnostic evaluation for the causes of pediatric acute liver failure: an opportunity for quality improvement. J Pediatr. 2009 Dec;155(6):801-806.e1. doi: 10.1016/j.jpeds.2009.06.005. Epub 2009 Jul 29.
• Rudnick DA, Dietzen DJ, Turmelle YP, Shepherd R, Zhang S, Belle SH, Squires R; Pediatric Acute Liver Failure Study Group. Serum alpha-NH-butyric acid may predict spontaneous survival in pediatric acute liver failure. Pediatr Transplant. 2009 Mar;13(2):223-30. doi: 10.1111/j.1399-3046.2008.00998.x. Epub 2008 Jul 17.
• Shneider BL, Rinaldo P, Emre S, Bucuvalas J, Squires R, Narkewicz M, Gondolesi G, Magid M, Morotti R, Hynan LS. Abnormal concentrations of esterified carnitine in bile: a feature of pediatric acute liver failure with poor prognosis. Hepatology. 2005 Apr;41(4):717-21.
• Squires RH Jr, Shneider BL, Bucuvalas J, Alonso E, Sokol RJ, Narkewicz MR, Dhawan A, Rosenthal P, Rodriguez-Baez N, Murray KF, Horslen S, Martin MG, Lopez MJ, Soriano H, McGuire BM, Jonas MM, Yazigi N, Shepherd RW, Schwarz K, Lobritto S, Thomas DW, Lavine JE, Karpen S, Ng V, Kelly D, Simonds N, Hynan LS. Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. J Pediatr. 2006 May;148(5):652-658.
• Sundaram SS, Alonso EM, Narkewicz MR, Zhang S, Squires RH; Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure. J Pediatr. 2011 Nov;159(5):813-818.e1. doi: 10.1016/j.jpeds.2011.04.016. Epub 2011 May 31.

• Responsible Party: Robert Squires, Jr., MD, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00248625
• Other Study ID Numbers: IRB #: 0608007; U01DK072146
• First Posted: Nov 4, 2005
• Last Update Posted: Jul 28, 2016
• Last Verified: Jun 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Robert Squires, Jr., MD, University of Pittsburgh: acute liver failure; hepatic encephalopathy; acetaminophen toxicity; N-acetylcysteine
• Additional relevant MeSH terms: Liver Failure; Hepatic Insufficiency; Hepatic Encephalopathy; Liver Failure, Acute; Brain Diseases; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

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

Arm/Group Title	Placebo	N-acetylcysteine (NAC)
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

Baseline Characteristics

Arm/Group Title	N-acetylcysteine (NAC)	Placebo	Total
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 Participants	92	92	184
Age (Count of Participants)
<=18 years	92 100%	92 100%	184 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	3.7	4.5	4.1
Sex: Female, Male (Count of Participants)
Female	45 48.9%	38 41.3%	83 45.1%
Male	47 51.1%	54 58.7%	101 54.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	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%
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 (participants) [Number]
Canada	2 2.2%	3 3.3%	5 2.7%
United States	61 66.3%	68 73.9%	129 70.1%
United Kingdom	29 31.5%	21 22.8%	50 27.2%
Coma Grade of Hepatic Encephalopathy (participants) [Number]
0-1	65 70.7%	68 73.9%	133 72.3%
2-4	27 29.3%	24 26.1%	51 27.7%

Outcome Measures

1. Primary Outcome

Title	Survival
Description	Spontaneous survival without transplant plus survival following transplantation
Time Frame	One year following randomization

Outcome Measure Data

Analysis Population Description

All participants who were enrolled in the study were included in the survival analysis

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
Number [Participants]	68 73.9%	76 82.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.19
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Spontaneous Recovery
Description	Survival without liver transplantation
Time Frame	One year following randomization

Outcome Measure Data

Analysis Population Description

All participants enrolled in study

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
Number [participants]	33 35.9%	49 53.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Cumulative Percent Incidence of Transplantation by 1 Year
Time Frame	Within 1 year of randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
Number [percentage of participants]	45 48.9%	35 38%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	Pepe and Mori test of CIF difference
	Comments

4. Secondary Outcome

Title	Length of Hospital Stay
Time Frame	Randomization to hospital discharge

Outcome Measure Data

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
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
Measure Participants	91	91
Median (Inter-Quartile Range) [days]	103	21

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments
	Method	Kruskal-Wallis
	Comments

5. Secondary Outcome

Title	Categorized Length of ICU Stay
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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
0 days	29 31.5%	34 37%
1 day	3 3.3%	4 4.3%
2 days	3 3.3%	4 4.3%
3 days	2 2.2%	0 0%
4 days	1 1.1%	3 3.3%
5 days	4 4.3%	3 3.3%
6 days	5 5.4%	3 3.3%
7 days	9 9.8%	14 15.2%
underwent LTx w/i 7 days of randomization	28 30.4%	22 23.9%
died w/o LTx w/i 7 days of randomization	8 8.7%	5 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments
	Method	Cochran-Armitage trend
	Comments

6. Secondary Outcome

Title	Number of Organ Systems Failing
Time Frame	Within 7 days of randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
0	44 47.8%	46 50%
1	21 22.8%	23 25%
2	15 16.3%	12 13%
3	11 12%	8 8.7%
4	1 1.1%	3 3.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Cochran-Armitage trend
	Comments

7. Secondary Outcome

Title	Highest Coma Grade of Hepatic Encephalopathy
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

Outcome Measure Data

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
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
Measure Participants	90	90
0	28 30.4%	27 29.3%
I	16 17.4%	21 22.8%
II	20 21.7%	19 20.7%
III	15 16.3%	17 18.5%
IV	11 12%	6 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.54
	Comments
	Method	Cochran-Armitage tren
	Comments

8. Secondary Outcome

Title	Infectious Complication
Time Frame	Within 7 days of randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
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
Measure Participants	92	92
Number [Participants]	20 21.7%	21 22.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	N-acetylcysteine (NAC), Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.86
	Comments
	Method	Chi-squared
	Comments

Adverse Events

Time Frame	Seven day randomization treatment period
Adverse Event Reporting Description	Regular investigator assessment
Arm/Group Title	N-acetylcysteine (NAC)		Placebo
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	N-acetylcysteine (NAC)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/92 (5.4%)		4/92 (4.3%)
Blood and lymphatic system disorders
Aplastic Anemia	1/92 (1.1%)		0/92 (0%)
Cardiac disorders
Bradycardiac episode	1/92 (1.1%)		0/92 (0%)
Bigeminy	0/92 (0%)		1/92 (1.1%)
Ear and labyrinth disorders
Hearing loss	0/92 (0%)		1/92 (1.1%)
Endocrine disorders
Hypoglycemia	1/92 (1.1%)		0/92 (0%)
Gastrointestinal disorders
Small intestine ulcerations	0/92 (0%)		1/92 (1.1%)
General disorders
Fever	0/92 (0%)		1/92 (1.1%)
Infections and infestations
Bacteremia	1/92 (1.1%)		0/92 (0%)
Epstein-Barr virus	1/92 (1.1%)		0/92 (0%)
Fever, chills, sinusitis	1/92 (1.1%)		0/92 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory distress	1/92 (1.1%)		0/92 (0%)
Other (Not Including Serious) Adverse Events
	N-acetylcysteine (NAC)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/92 (20.7%)		16/92 (17.4%)
Cardiac disorders
Arrhythmia	1/92 (1.1%)		4/92 (4.3%)
Bradycardia	1/92 (1.1%)		1/92 (1.1%)
Eye disorders
Dilated and fixed pupils	1/92 (1.1%)		0/92 (0%)
General disorders
Sleepiness	1/92 (1.1%)		1/92 (1.1%)
High Fever	1/92 (1.1%)		1/92 (1.1%)
Infections and infestations
Infection	11/92 (12%)		8/92 (8.7%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/92 (1.1%)		0/92 (0%)
Aspiration	1/92 (1.1%)		0/92 (0%)
Pleural effusion	1/92 (1.1%)		0/92 (0%)
Skin and subcutaneous tissue disorders
Rash	4/92 (4.3%)		2/92 (2.2%)
Vascular disorders
Hypertension	1/92 (1.1%)		0/92 (0%)

Limitations/Caveats

[Not Specified]

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.