Study protocol: HiSNAP trial - a multi-centre, randomised, open label, blinded end-point, safety and efficacy trial of conventional (300mg/kg) versus higher doses of acetylcysteine (450mg/kg and 600mg/kg) in patients with paracetamol overdose in the United Kingdom

IntroductionIn overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the United Kingdom receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggests that this dose may be insufficient in some patients (particularly those taking a large overdose). Methods and analysisA multi-centre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced 19 Feb 2024, and is anticipated to run for approximately two years. This is a three-group dose finding trial, in which participants are assigned in a 1:1:1 ratio to either standard NAC (300mg/kg), or higher doses of 450mg/kg (Group 1) and 600mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant, will HiSNAP Group 1 be tested against Standard NAC. Ethics and disseminationThe HiSNAP trial has been approved by East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences, and linked on isrctn.com. Registration detailsISRCTN 17516192 Strengths and limitations of this studyO_LIThe study will systematically collect data to assess the safety and efficacy of higher acetylcysteine doses and the current standard dose. C_LIO_LIThe study primary endpoint is measurable in every patient, in contrast with paracetamol overdose trials examining liver injury (which only occurs in approximately 10% of patients). C_LIO_LIThe study has pragmatic inclusion criteria - the decision that the patient requires acetylcysteine lies with the clinical team. C_LIO_LIThe study seeks to minimise imbalances between treatment groups by stratifying randomisation according to whether a patient is at high risk of liver injury after overdose. C_LIO_LIThe study is limited by the primary outcome being biomarker-based. Any benefits on clinical outcomes will still require confirmation. C_LI