Introduction: In 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 analysis: A 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 dissemination: The 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 details: ISRCTN 17516192

All of the HiSNAP Trial Investigators acknowledge that work for the HiSNAP Trial is supported by Chief Scientist Office funding (TCS/21/04). JD: MRC funding (and patent filed) for an in vitro diagnostic which could be a companion diagnostic, MRC funding for another clinical trial for treatment of paracetamol overdose, scientific advisory board member for EU funded TransBioLine consortium. MG: expert advisor to BMJ Best Practice (honorarium), member of RCEM Toxicology advisory group. CH: grants from the Centre for Precision Cell Therapy for the Liver, honoraria from Elsevier, support for meetings and travel from Royal College of Emergency Medicine (RCEM), member of RCEM Toxicology advisory group, editor for a BMJ Group medical journal. SI: grant from Sir Jules Thorn Charitable Trust. SI/KO: grants from Jon Moulton Trust/National Institute for Health Research/British Heart Foundation/University of Edinburgh. KO: support for attending meetings from Universities of Edinburgh and Nottingham, membership of UK Trial Managers Network Executive Committee, Membership of University of Edinburgh Clinical Trials MSc steering committee. CJW: recipient of Chief Scientist Office and Medical Research Council grant funding to his institution.

ISRCTN 17516192

The HiSNAP trial is an investigator-led study, funded by the Chief Scientist Office, part of the Scottish Government Health Directorates (reference TCS/21/04). For the purpose of open access, the author has applied a creative commons attribution (CC BY) licence to any author accepted manuscript version arising. The investigators additionally acknowledge general expertise and support supplied pro bono by the Centre for Precision Cell Therapy for the Liver, a research centre funded by the Chief Scientist Office under the Precision Medicine Alliance for Scotland scheme.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and was approved by East Midlands (Derby) Research Ethics Committee 26 Sep 2023 (reference 23/EM/0129), NHS Lothian Research and Development department, and the MHRA. Good Clinical Practice regulations will be followed and written informed consent will be obtained from all participants.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Results will be disseminated by peer-reviewed publication, conferences, and linked on isrctn.com. Publication content will follow the Reporting of surrogate endpoints in randomised controlled trial reports (CONSORT-Surrogate) Extension of the CONSORT 2010 Statement. Ownership of data arising from this study resides with the study team at the Sponsor Organisation. The study team will follow the International Committee of Medical Journal Editors guidelines on authorship. Requests for data access should be sent to the corresponding author.