N-acetylcysteine in Non-Acetaminophen Pediatric Acute Liver Failure

Phase 3

Completed

• Conditions: Acute Liver Failure; Hepatic Encephalopathy
• Interventions: Drug: Placebo; Drug: N-acetylcysteine

• Registration Number: NCT00248625
• Lead Sponsor: University of Pittsburgh

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.

Study Timeline

• Study Start: 2000-01
• Study First Submitted: 2005-11-03
• Study First Submitted QC: 2005-11-03
• Study First Posted: 2005-11-04
• Primary Completion: 2009-09
• Study Completion: 2010-10
• Results First Submitted: 2016-02-19
• Status Verified: 2016-06
• Results First Submitted QC: 2016-06-16
• Last Update Submitted: 2016-06-16
• Results First Posted: 2016-07-28
• Last Update Posted: 2016-07-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 184

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
placebo	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
N-acetylcysteine (NAC)	N-acetylcysteine	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

Primary Outcome Measures

Name	Time	Method
Survival	One year following randomization	Spontaneous survival without transplant plus survival following transplantation

Secondary Outcome Measures

Name	Time	Method
Cumulative Percent Incidence of Transplantation by 1 Year	Within 1 year of randomization
Spontaneous Recovery	One year following randomization	Survival without liver transplantation
Length of Hospital Stay	Randomization to hospital discharge
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.
Number of Organ Systems Failing	Within 7 days of randomization
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.
Infectious Complication	Within 7 days of randomization

Trial Locations

Locations (20)

Children's Memorial Hospital; 🇺🇸 Chicago, Illinois, United States

King's College Hospital (London, UK); 🇬🇧 London, United Kingdom

Children's Hospital of Pittsburgh of UPMC; 🇺🇸 Pittsburgh, Pennsylvania, United States

Columbia-Presbyterian; 🇺🇸 New York, New York, United States

Emory University, Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Harvard University, Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Johns Hopkins University; 🇺🇸 Baltimore, Maryland, United States

Mount Sinai Hospital; 🇺🇸 New York, New York, United States

Children's Medical Center of Dallas; 🇺🇸 Dallas, Texas, United States

Birmingham Children's Hospital; 🇬🇧 Birmingham, United Kingdom

St. Louis Children's Hospital; 🇺🇸 St. Louis, Missouri, United States

Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada

University of California, San Francisco; 🇺🇸 San Francisco, California, United States

Riley Children's Hospital; 🇺🇸 Indianapolis, Indiana, United States

University of Colorado, Denver Children's Hospital; 🇺🇸 Denver, Colorado, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

University of Cincinnati, Cincinnati Children's Hospital; 🇺🇸 Cincinnati, Ohio, United States

Baylor College of Medicine; 🇺🇸 Houston, Texas, United States

University of Washington; 🇺🇸 Seattle, Washington, United States