Title: Statins for Improving orGaN outcomE in Transplantation (SIGNET)
Funder: Department of Health and Social Care

Abstract: Aims of Research: _x000D_ To investigate whether giving deceased organ donors a single dose of the drug Simvastatin, very inexpensive and safe, is beneficial for transplant recipients. _x000D_ Background: _x000D_ All organs removed from donors have already suffered a degree of damage. As the brain dies (and all of these donors are brain-stem dead) chemicals are released which cause an “inflammation” of the whole body. Measurements of this “inflammation” link to how well the organs function in the recipient after transplant. _x000D_ In parallel, cholesterol-lowering drugs “statins” have benefits across a range of health problems which go beyond the benefits on cholesterol., Statins damp down inflammation in the body and in organs. Statins protect the lungs and kidneys in a range of illnesses. _x000D_ _x000D_ Recently, transplant doctors in Finland linked this information in an innovative clinical study. Organ donors who were about to donate their heart were randomised to receive a dose of a statin. They randomised 84 donors so 42 received the drug. After the transplant, the recipients who received a heart from a donor who had statins had less heart damage. The numbers were modest, and there was no survival advantage. There was a small benefit for lung and liver recipients. There are no disadvantage in receiving any organ from a donor who had received the drug. _x000D_ _x000D_ Clinical Problem: _x000D_ A significant number of hearts and other organs offered for transplant by the donor family are not used; for the heart, this figure is about 75%. The reason for this is that poor function of the donor heart in the recipient is by far the most common cause of death post transplant. Any step in the donor which might improve the transplanted heart could have a major benefit to the recipient. The same principle applies to all the other organs transplanted. _x000D_ _x000D_ Trial Design and Methods _x000D_ We plan to enrol 650 adult brain-dead donors across the UK per year in a randomised controlled trial. Half of donors will receive the drug (in addition to standard donor care), compared to the other half of donors who will receive standard care only. The drug is given through a tube running into the stomach, already present in 80% of donors, but required to be placed in the other 20%. The drug will be given as soon as the donor family have consented to both organ donation and involvement of their loved one in research. _x000D_ _x000D_ Half of all the recipients will receive a heart from a donor given the drug. Transplant results will be followed, focussing on the heart recipients. We will also look in detail at the function of kidneys, livers, lungs and pancreas, comparing what happens in those who received the drug-treated organs, and those who did not. This data is already collected in the national transplant database. No extra data or blood samples will be needed. _x000D_ _x000D_ Patient and Public Involvement (PPI) _x000D_ A key part of this study is that consent is obtained from the donor family. We do not know who will be the recipient when the drug is given, so it is impossible to have consent from the recipient in advance. For all organ types, recipients would be informed that their donor might have received a statin, with the evidence is that there is no risk and there may be some benefit. _x000D_ _x000D_ This concept has received unanimous support at three meetings of patient and public representatives. Throughout the trial patient and public perspective will continue to be represented through an annual PPI Panel and 2 Co-Applicants on the Trial Steering Committee.

Lay abstract: Summary of Research (abstract) _x000D_ Design: This is a multi-centre, single-blind prospective, group sequential, randomised controlled trial. Randomisation will be in a 1:1 ratio and will be stratified according to whether the donor was receiving statin therapy at ICU admission. Randomisation will not be stratified by transplanting centre (unknown at the time) or donation hospital (standard donor management applies at all hospitals and there is no evidence that donor hospital influences recipient outcomes). _x000D_ Setting: This study will be undertaken at up to 80 major donation hospitals (defined as > 6 organ donors per year) and will capitalise on infrastructure unique to the UK to deliver cost effective research in organ donation. We have a robust network of Clinical Leads for Organ Donation (intensivists at hospitals with high donor numbers), a cohort of Specialist Nurses in Organ Donation (SNODs) who have extensive training in discussing consent with donor families under the most distressing of circumstances, a national organ matching service and a national transplant registry which includes detailed recipient outcomes (UK Transplant Registry). After approach for consent for organ donation, research consent from donor families will be requested by the SNOD, who will subsequently manage the online randomization system established by the clinical trials unit. _x000D_ Population: Adult, brain-stem dead donors at major organ donation centres in the UK _x000D_ Intervention: A single dose of 80mg Simvastatin, given via nasogastric tube (already in place in >80% of donors) will be given as soon as possible after obtaining consent from the donor family _x000D_ Control group treatment: The standard donor management protocol, will ensure that treatment will be similar in all respects other than the intervention. _x000D_ Outcomes: The Primary Outcome will be a composite of mortality, cardiac mechanical support or renal replacement therapy within 30 days following heart transplant. Secondary outcomes are important clinical and safety organ specific transplant outcomes routinely collected by the UK Transplant Registry for all solid organs transplanted from donors in the study. _x000D_ _x000D_ Follow up: 30 days, 3 months and up to 1-year post transplant _x000D_ Sample size: 1300 per group, 2600 patients in total. _x000D_ _x000D_ Project time frames:Study set up will require 6 months, followed by a recruitment phase of 48 months, with an additional 15 months for follow up and close out.The total project duration is 69 months. Randomisation of donors at designated donation hospitals will begin in April 2021. Analysis of consent and inclusion will be continuous, with review at the end of year 1. Recruitment will be monitored on a monthly basis by the Trial Management Group, with planned interim analysis at two and three years for harm, benefit and futility.Recruitment will run for a total of 48 months, followed by a 12 month follow up period for collection of all organ primary and secondary outcomes. Final analyses and preparation of the final report will be completed by the end of the contractual period (June 2026).

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR;INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL;RENAL AND UROGENITAL;RESPIRATORY