N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

This study has been completed.

Sponsor:

Collaborator:

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

Information provided by (Responsible Party):

Robert Squires, Jr., University of Pittsburgh

ClinicalTrials.gov Identifier:

NCT00248625

First received: November 3, 2005

Last updated: June 16, 2016

Last verified: June 2016

History of Changes

Results First Received: February 19, 2016

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator); Primary Purpose: Treatment
Conditions:	Acute Liver Failure Hepatic Encephalopathy
Interventions:	Drug: N-acetylcysteine Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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Reporting Groups

	Description
Placebo	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.
N-acetylcysteine (NAC)	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.

Description

Placebo

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.

N-acetylcysteine (NAC)

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.

Participant Flow: Overall Study

	Placebo	N-acetylcysteine (NAC)
STARTED	92	92
COMPLETED	92	90
NOT COMPLETED	0	2
Withdrawal by Subject	0	2

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants who were randomized were included in the baseline analysis.

Reporting Groups

	Description
N-acetylcysteine (NAC)	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.
Placebo	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	Total of all reporting groups

Description

N-acetylcysteine (NAC)

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.

Placebo

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

Total of all reporting groups

Baseline Measures

	N-acetylcysteine (NAC)	Placebo	Total
Number of Participants [units: participants]	92	92	184
Age [units: participants]
<=18 years	92	92	184
Between 18 and 65 years	0	0	0
>=65 years	0	0	0
Age [units: years] Median (Inter-Quartile Range)	3.7 (0.8 to 10.5)	4.5 (1.0 to 9.5)	4.1 (0.9 to 10.0)
Gender [units: participants]
Female	45	38	83
Male	47	54	101
Race (NIH/OMB) [units: participants]
American Indian or Alaska Native	0	1	1
Asian	3	5	8
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	15	15	30
White	68	65	133
More than one race	3	4	7
Unknown or Not Reported	3	2	5
Region of Enrollment [units: participants]
Canada	2	3	5
United States	61	68	129
United Kingdom	29	21	50
Coma Grade of Hepatic Encephalopathy ^[1] [units: participants]
0-1	65	68	133
2-4	27	24	51

[1]	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]

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.

Outcome Measures

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1. Primary:

Survival [ Time Frame: One year following randomization ]

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2. Secondary:

Spontaneous Recovery [ Time Frame: One year following randomization ]

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3. Secondary:

Cumulative Percent Incidence of Transplantation by 1 Year [ Time Frame: Within 1 year of randomization ]

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4. Secondary:

Length of Hospital Stay [ Time Frame: Randomization to hospital discharge ]

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5. Secondary:

Categorized Length of ICU Stay [ Time Frame: Within 7 days of randomization ]

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6. Secondary:

Number of Organ Systems Failing [ Time Frame: Within 7 days of randomization ]

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7. Secondary:

Highest Coma Grade of Hepatic Encephalopathy [ Time Frame: Within 7 days of randomization ]

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8. Secondary:

Infectious Complication [ Time Frame: Within 7 days of randomization ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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More Information

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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:

Name/Title: Robert H. Squires, Jr.
Organization: University of Pittsburgh
phone: 412-692-8648
e-mail: squiresr@upmc.edu

Publications:

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.

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.

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.

Alonso EM. Acute liver failure in children: the role of defects in fatty acid oxidation. Hepatology. 2005 Apr;41(4):696-9. Review.

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.

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., University of Pittsburgh
ClinicalTrials.gov Identifier:	NCT00248625 History of Changes
Other Study ID Numbers:	IRB #: 0608007 U01DK072146 ( US NIH Grant/Contract Award Number )
Study First Received:	November 3, 2005
Results First Received:	February 19, 2016
Last Updated:	June 16, 2016
Health Authority:	United States: Food and Drug Administration

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