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N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

Primary Purpose

Acute Liver Failure, Hepatic Encephalopathy

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
N-acetylcysteine
Placebo
Sponsored by
University of Pittsburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Liver Failure focused on measuring acute liver failure, hepatic encephalopathy, acetaminophen toxicity, N-acetylcysteine

Eligibility Criteria

undefined - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of California, San Francisco
  • University of Colorado, Denver Children's Hospital
  • Emory University, Children's Healthcare of Atlanta
  • Children's Memorial Hospital
  • Riley Children's Hospital
  • Johns Hopkins University
  • Harvard University, Boston Children's Hospital
  • University of Michigan
  • St. Louis Children's Hospital
  • Mount Sinai Hospital
  • Columbia-Presbyterian
  • University of Cincinnati, Cincinnati Children's Hospital
  • Children's Hospital of Philadelphia
  • Children's Hospital of Pittsburgh of UPMC
  • Children's Medical Center of Dallas
  • Baylor College of Medicine
  • University of Washington
  • Hospital for Sick Children
  • Birmingham Children's Hospital
  • King's College Hospital (London, UK)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

N-acetylcysteine (NAC)

placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

Survival
Spontaneous survival without transplant plus survival following transplantation

Secondary Outcome Measures

Spontaneous Recovery
Survival without liver transplantation
Cumulative Percent Incidence of Transplantation by 1 Year
Length of Hospital Stay
Categorized Length of ICU Stay
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.
Number of Organ Systems Failing
Highest Coma Grade of Hepatic Encephalopathy
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.
Infectious Complication

Full Information

First Posted
November 3, 2005
Last Updated
June 16, 2016
Sponsor
University of Pittsburgh
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT00248625
Brief Title
N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure
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 Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Completed
Study Start Date
January 2000 (undefined)
Primary Completion Date
September 2009 (Actual)
Study Completion Date
October 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Pittsburgh
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Liver Failure, Hepatic Encephalopathy
Keywords
acute liver failure, hepatic encephalopathy, acetaminophen toxicity, N-acetylcysteine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
184 (Actual)

8. Arms, Groups, and Interventions

Arm Title
N-acetylcysteine (NAC)
Arm Type
Active Comparator
Arm Description
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
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
N-acetylcysteine
Other Intervention Name(s)
Mucomyst
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
dextrose in water
Intervention Description
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.
Primary Outcome Measure Information:
Title
Survival
Description
Spontaneous survival without transplant plus survival following transplantation
Time Frame
One year following randomization
Secondary Outcome Measure Information:
Title
Spontaneous Recovery
Description
Survival without liver transplantation
Time Frame
One year following randomization
Title
Cumulative Percent Incidence of Transplantation by 1 Year
Time Frame
Within 1 year of randomization
Title
Length of Hospital Stay
Time Frame
Randomization to hospital discharge
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
Title
Number of Organ Systems Failing
Time Frame
Within 7 days of randomization
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
Title
Infectious Complication
Time Frame
Within 7 days of randomization

10. Eligibility

Sex
All
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert H Squires, M.D.
Organizational Affiliation
Children's Hospital of Pittsburgh, University of Pittsburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
University of Colorado, Denver Children's Hospital
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
Country
United States
Facility Name
Emory University, Children's Healthcare of Atlanta
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Children's Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Riley Children's Hospital
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Harvard University, Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
St. Louis Children's Hospital
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Mount Sinai Hospital
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Columbia-Presbyterian
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
University of Cincinnati, Cincinnati Children's Hospital
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Children's Hospital of Pittsburgh of UPMC
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Children's Medical Center of Dallas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Birmingham Children's Hospital
City
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
King's College Hospital (London, UK)
City
London
ZIP/Postal Code
SE59RS
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
19643443
Citation
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.
Results Reference
background
PubMed Identifier
18643912
Citation
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.
Results Reference
background
PubMed Identifier
16950959
Citation
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. doi: 10.1542/peds.2006-0069.
Results Reference
background
PubMed Identifier
16737880
Citation
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. doi: 10.1016/j.jpeds.2005.12.051.
Results Reference
background
PubMed Identifier
15789368
Citation
Alonso EM. Acute liver failure in children: the role of defects in fatty acid oxidation. Hepatology. 2005 Apr;41(4):696-9. doi: 10.1002/hep.20680. No abstract available.
Results Reference
background
PubMed Identifier
15791615
Citation
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. doi: 10.1002/hep.20631.
Results Reference
background
PubMed Identifier
21621221
Citation
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.
Results Reference
background

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N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

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