N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

NCT00248625 | Completed Phase 3 Results DMC

• 2 other identifiers: IRB #: 0608007U01DK072146
• Study Type: interventional
• Target: 184
• Locations: 3 countries
• Sites: 20

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.

Conditions

Acute Liver Failure; Hepatic Encephalopathy

Keywords

acute liver failure; hepatic encephalopathy; acetaminophen toxicity; N-acetylcysteine

Outcome Measures

Primary Outcomes (1)

• Survival

  Spontaneous survival without transplant plus survival following transplantation

  One year following randomization

Secondary Outcomes (7)

• Spontaneous Recovery

  One year following randomization

• Cumulative Percent Incidence of Transplantation by 1 Year

  Within 1 year of randomization

• Length of Hospital Stay

  Randomization to hospital discharge

• Categorized Length of ICU Stay

  Within 7 days of randomization

• Number of Organ Systems Failing

  Within 7 days of randomization

Study Arms (2)

N-acetylcysteine (NAC)

ACTIVE COMPARATOR

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

placebo

PLACEBO COMPARATOR

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

Interventions

N-acetylcysteine 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.

Also known as: Mucomyst

N-acetylcysteine (NAC)

Placebo 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.

Also known as: dextrose in water

placebo

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (20)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado, Denver Children's Hospital

Denver, Colorado, 80218, United States

Location

Emory University, Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

Children's Memorial Hospital

Chicago, Illinois, 60614, United States

Location

Riley Children's Hospital

Indianapolis, Indiana, 46202, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Harvard University, Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

Columbia-Presbyterian

New York, New York, 10032, United States

Location

University of Cincinnati, Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Children's Medical Center of Dallas

Dallas, Texas, 75235, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of Washington

Seattle, Washington, 98105, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

King's College Hospital (London, UK)

London, SE59RS, United Kingdom

Location

Related Publications (7)

• 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.

  PMID: 19643443 BACKGROUND

• 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.

  PMID: 18643912 BACKGROUND

• 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.

  PMID: 16950959 BACKGROUND

• 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.

  PMID: 16737880 BACKGROUND

• 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.

  PMID: 15789368 BACKGROUND

• 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.

  PMID: 15791615 BACKGROUND

• 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.

  PMID: 21621221 BACKGROUND

MeSH Terms

Conditions

Liver Failure, Acute; Hepatic Encephalopathy

Interventions

Acetylcysteine; Glucose; Water

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; Hexoses; Monosaccharides; Sugars; Carbohydrates; Hydroxides; Alkalies; Inorganic Chemicals; Anions; Ions; Electrolytes; Oxides; Oxygen Compounds

Results Point of Contact

• Title: Robert H. Squires, Jr.
• Organization: University of Pittsburgh

squiresr@upmc.edu

412-692-8648

Study Officials

• Robert H Squires, M.D.

  Children's Hospital of Pittsburgh, University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: November 3, 2005
• First Posted: November 4, 2005
• Study Start: January 1, 2000
• Primary Completion: September 1, 2009
• Study Completion: October 1, 2010
• Last Updated: July 28, 2016
• Results First Posted: July 28, 2016

Record last verified: 2016-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (17); GB (2); CA (1)