N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

NCT ID: NCT00248625

Last Updated: 2016-07-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 184 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-01-31
• Study Completion Date: 2010-10-31

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.

Conditions

Acute Liver Failure; Hepatic Encephalopathy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

N-acetylcysteine

Intervention Type: DRUG

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.

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Mucomyst; dextrose in water

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

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: collaborator

University of Pittsburgh

OTHER

Sponsor Role: lead

Responsible Party

Robert Squires, Jr.

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Robert H Squires, M.D.

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Pittsburgh, University of Pittsburgh

Locations

University of California, San Francisco

San Francisco, California, United States

University of Colorado, Denver Children's Hospital

Denver, Colorado, United States

Emory University, Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Children's Memorial Hospital

Chicago, Illinois, United States

Riley Children's Hospital

Indianapolis, Indiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Harvard University, Boston Children's Hospital

Boston, Massachusetts, United States

University of Michigan

Ann Arbor, Michigan, United States

St. Louis Children's Hospital

St Louis, Missouri, United States

Mount Sinai Hospital

New York, New York, United States

Columbia-Presbyterian

New York, New York, United States

University of Cincinnati, Cincinnati Children's Hospital

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Children's Medical Center of Dallas

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Washington

Seattle, Washington, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Birmingham Children's Hospital

Birmingham, , United Kingdom

King's College Hospital (London, UK)

London, , United Kingdom

Countries

United States; Canada; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 19643443 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18643912 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16950959 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 16737880 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15789368 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15791615 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21621221 (View on PubMed)

Other Identifiers

U01DK072146

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB #: 0608007

Identifier Type: -

Identifier Source: org_study_id