Introduction: SIGNET is a single-blind, randomised controlled trial (RCT) recruiting 2600 organ donors diagnosed dead by neurological criteria, across 76 large hospital trusts in the United Kingdom (UK). The intervention is a single dose of Simvastatin, a safe, affordable, and commonly used drug. The trial utilises the UK’s unique infrastructure for organ donation and transplantation, with specialist nurses for organ donation (SNODs) seeking family consent and randomising donors. SIGNET uses UK Transplant Registry (UKTR) data for all recipient outcomes and is a pragmatic trial, assessing not only whether Simvastatin will help limit damage in donor hearts, but also whether it is feasible to deliver an interventional organ donor trial using a risk-adapted approach.

Methods: The trial team held discussions with the Medicines and Healthcare products Regulatory Agency (MHRA) and Health Research Authority to consider risk-adapted approaches appropriate for a study in deceased patients during the organ donation process and to review applicable trial regulations in this context. There were several challenges to overcome including the volume of sites involved, applicable consent for organ donors and recipients, GCP training for SNODs, workload for site research teams and Clinical Trial of an Investigational Medicinal Product (CTIMP) status.

Results: Following these discussions, SIGNET is not considered a CTIMP, and the SIGNET team gained approvals and proceeded with site set-up. Using novel approaches developed for the pandemic for site training and a GCP proportionate approach for SNODs, over 500 people (SNODs and research teams) were trained over a 4-month period, with 79 trusts (126 hospitals) currently open to recruitment. Randomisation, which had not previously been performed by SNODs, has been trouble free and sites have reported very little burden on them.

Discussion: SIGNET will be the largest global RCT in organ donation, benefitting from the unique strengths of the UK NHS infrastructure. We have utilised the MHRA’s Innovation office to set precedents for interventional organ donation trials and implement risk-adapted approaches. Using a GCP proportionate approach and methods developed during the pandemic, we trained and set up numerous teams in a short period of time whilst minimising burden on site research departments. We are utilising the SNODs’ skills and knowledge of consent to reach a large recruitment target. The centralised nature of the UKTR ensures high data completeness and a low burden on site research teams. These approaches could encourage further research into organ donation and help embed organ donation research into normal practice.