A multicentre study of the safety and efficacy of N-acetylcysteine in the treatment of acute liver failure in paediatric patients not caused by acetaminophen

ISRCTN	ISRCTN36658311
DOI	https://doi.org/10.1186/ISRCTN36658311
ClinicalTrials.gov number	NCT00248625
Secondary identifying numbers	6201

Submission date: 12/05/2010
Registration date: 12/05/2010
Last edited: 14/07/2014

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Prof Anil Dhawan
Scientific

Department of Liver Studies and Transplantation
Strand
London
WC2R 2LS
United Kingdom

Study information

Study design	Multicentre randomised interventional treatment trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Other
Study type	Treatment
Scientific title
Study acronym	PALF
Study objectives	Acute liver failure (ALF) is a rare form of liver disease in children. The condition leads to failure of the function of the liver in a child with no previous history of liver disease. The causative agents include infections, drugs and sometimes metabolic defects that present for the first time as liver failure. However, the cause of the liver failure could only be identified in one-third of the patients. There is no accepted specific treatment for ALF other than general supportive measures such as maintenance of blood sugar levels, prevention of superadded infections, administration of blood products, measures to reduce brain swelling and assisted breathing in the intensive care unit. In patients with severe disesase, liver transplantation is the only effective treatment. The purpose of this study is to test whether a drug called N-acetylcysteine (NAC) improves outcome of patients with ALF. This drug is used as an antidote in patients with paracetamol overdose who usually develop liver failure. This drug has been very helpful in improving the survival of patients where overdose is likely to be fatal. N-acetylcysteine reduces cell injury induced by oxidative stress in liver failure not only in liver but other organs also. In a small number of adults in our hospital with liver failure not related to paracetamol overdose an improvement in various parameters of body function like blood pressure and oxygen utilisation was observed after administration of NAC. This drug has also been shown to improve cell function in situations of multi-organ failure not caused by liver failure. However a more recent study from Edinburgh failed to demonstrate these observations. This drug has been used without a definitive evidence of its efficacy in few centres (including ours) in the management of liver failure. This multinational randomised controlled trial will help to establish the safety and efficacy of this drug.
Ethics approval(s)	MREC approved (ref: 02-186)
Health condition(s) or problem(s) studied	Topic: Medicines for Children Research Network; Subtopic: All Diagnoses; Disease: All Diseases
Intervention	The study drug or placebo will be given as a 7-day continuous intravenous infusion to children with acute liver failure not due to acute acetaminophen toxicity. Study drug: intravenous N-acetylcysteine Total duration of therapy: 7 days. Duration may be less in the event of spontaneous recovery or liver transplantation.
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	N-acetylcysteine
Primary outcome measure	Comparison of survival without liver transplant
Secondary outcome measures	1. Length of intensive care unit and hospital stay 2. Number of organ systems failures
Overall study start date	01/01/2003
Completion date	01/12/2010

Eligibility

Participant type(s)	Patient
Age group	Child
Upper age limit	18 Years
Sex	Not Specified
Target number of participants	Planned sample size: 184; UK sample size: 28
Key inclusion criteria	Enrolment in PALF registry: 1. Evidence of acute liver injury 2. International normalised ratio (INR) greater than or equal to 1.5 or prothrombin time (PT) greater than or equal to 15 with encephalopathy, or INR greater than or equal to 2.0 or PT greater than or equal to 20 with or without encephalopathy 3. Aged less than 18 years, either sex 4. Informed consent, obtained from the patient or parent
Key exclusion criteria	1. Acute paracetomol toxicity 2. Patient on N-acetylcysteine or received N-acetylcysteine during the course of this illness 3. Pregnancy 4. Known malignancy 5. Patient is on a liver support device 6. Sepsis 7. Signs of cerebral herniation 8. Intractable hypotension
Date of first enrolment	01/01/2003
Date of final enrolment	01/12/2010

Locations

Countries of recruitment

Canada
England
United Kingdom
United States of America

Study participating centre

Department of Liver Studies and Transplantation

London
WC2R 2LS
United Kingdom

Sponsor information

King's College Hospital NHS Foundation Trust (UK)
Hospital/treatment centre

Denmark Hill
London
SE5 9RS
England
United Kingdom

Website	http://www.kch.nhs.uk/
"ROR"	https://ror.org/01n0k5m85

Funders

Funder type

Government

National Institutes of Health (NIH) (USA)
Government organisation / National government

Alternative name(s): Institutos Nacionales de la Salud, US National Institutes of Health, NIH
Location: United States of America

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/04/2013		Yes	No