Introduction: Acute Liver Failure (ALF) has no effective treatment other than liver transplantation, and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs. Methods and analysis: A single centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Ethics and dissemination: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East - York Research Ethics Committee (reference 23/NE/0019), NHS Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication. Trial registration number: ISRCTN 12637839.

All authors acknowledge that work for the MAIL Trial and publication of this manuscript is supported by MRC and CSO funding. GA: consulting fees from Clinipace, GSK, Amryth, Pfizer, DNDi, BenevolentAI Bio, PureTech LYT, Merck, Agios, Astra Zeneca, Suzhou MDCE. JCa: advisor to, founding member of, and stock options in Resolution Therapeutics, multiple patents related to delivery of macrophage cell therapy. JD: MRC funding (and patent filed) for an in vitro diagnostic which could be a companion diagnostic, CSO funding for another clinical trial for treatment of paracetamol overdose, scientific advisory board member for EU funded TransBioLine consortium. RF: grants or contracts from Takeda and Kezar. SF: consulting fees for Cytotheryx and Resolution Therapeutics, honoraria received from Japanese Society for Regenerative Medicine, multiple patents related to macrophage cell therapy, advisory board member for Cytotheryx, stock options, founder, and director of Resolution Therapeutics. 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. ARo: independent statistician for other clinical trials.

ISRCTN12637839

This work is supported by the Medical Research Council (MRC) [MR/T044802/1]; and The Centre for Precision Cell Therapy for the Liver which was funded by the Chief Scientist Office (CSO) of the Scottish Government Health Directorates [PMAS/21/07]. For the purpose of open access, the author has applied a creative commons attribution (CC BY) licence to any author accepted manuscript version arising.

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 has been approved by North East - York Research Ethics Committee (reference 23/NE/0019), 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).

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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 CONSORT-DEFINE reporting guidance extension for dose-finding studies. Ownership of data arising from this study resides with the study team and their respective employers. 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.