Title: Efficacy and mechanism of sentinel skin flap reduction of solid organ (lung) transplant rejection: A randomised controlled trial (SENTINEL)
Funder: Medical Research Council

Abstract: Transplanted organs such as lungs, hearts, kidneys and pancreases are subject to attack by the immune system causing rejection of the transplanted organ. Rejection is prevented by immunosuppression medication that interferes with the body’s immune system and hinders rejection. Despite these medications rejection still occurs. If rejection is not detected and treated early enough the transplanted organ scars and stops working. Detecting rejection is difficult as it does not have specific features. In lung transplants attempts are made to detect rejection by very frequent hospital visits for chest x-rays, blood tests and biopsies of the transplanted lung. These tests are performed very regularly or of the patient has symptoms of lung disease such as coughing. All these tests can show are if there is inflammation but there is no specific measure of rejection until the rejection is very severe. We discovered when we were doing intestinal transplants which included a patch of skin as well that the skin displayed a easily visible rash when rejection was occurring, and that this sign was present before the intestine transplant rejected. The skin was visible continuously, so we did not have to rely on intermittent biopsies or other tests, but only performed these when the skin indicated there was rejection. As a result of this we began a trial, transplanting a patch of skin when a patient had a pancreas and kidney transplant. Our results show this transplanted skin also acts as a monitor for rejection in pancreas and kidney transplants. In both types of transplant having skin transplanted as well seemed to protect the organ from rejection. We wish to repeat this study in lung transplants to see if a skin transplant can act as a rejection monitor for heart transplants so that we can avoid the regular tests and hospital visits, reduce the immune suppression drug levels, and avoid rejection injury to the transplanted lung. We aim to recruit 152 adults waiting for a lung transplant from the five NHS lung transplant hospitals in England. All eligible patients will be sent a letter of invitation and a patient information sheet. If they are interested in participating in the study, they will be contacted by telephone by one of the research team and told details about the study. The participants that agree to take part will be randomly allocated either to receive only their lung transplant or their lung transplant along with a skin transplant from the same donor. The skin transplant will be a small patch of skin from the undersurface of the forearm. We will teach the patients how to examine the skin and how to contact us if a rash appears, so that we can take a tiny biopsy from the skin to confirm rejection and treat it. Apart from the addition of the skin patch (flap) transplant, all other treatment and care will be the same and patients will come back to clinic for their usual follow-up visits. Consultation with patient groups and transplant charities has taken place and patients will continue to be involved throughout the running of the study. The findings will be presented at national and international transplant meetings and will be published in a high-impact scientific journal. All patients taking part in the study will be informed of the findings via the study website. We hope that the study will have significant impact by reducing the number of tests and the risk of rejection for patients undergoing a solid organ transplant.

Lay abstract: Research Question: In solid organ transplantation (SOT) does the simultaneous transplantation of a skin flap from the same donor reduce the risk of rejection and thus improve the survival of the organ transplant?_x000D_ Background: 4,300 patients a year receive a SOT in the UK. Recipients take lifelong immunosuppressive medication to avoid rejection of the transplanted organ. Despite immunosuppression, rejection is a problem and must be treated early to prevent chronic organ damage or loss. However, diagnosis of early rejection is difficult to discriminate from infection or other causes, and signs of rejection occur late in the process. Use of a continuously visible SSF (SSF) from the same donor may allow early detection and treatment of rejection. The skin shows a visible rash with early rejection providing easy continuous immune-monitoring. This facilitates earlier detection and treatment of rejection, before organ injury, prolonging organ survival and may even permit titratable reduction of immunosuppression and reduction in invasive tests. Results from intestinal and pancreas/kidney transplant studies in Oxford suggest that transplant of a SSF is safe and adds value in diagnosing rejection; recipients had a significantly lower than expected rate of transplant organ rejection. This novel technique should be investigated in other SOTs. _x000D_ Aims: We aim to establish if combining a simultaneous SSF transplant with a SOT reduces rejection in the transplanted organ, protects it from immunological injury leading to improved longer-term outcomes, and to determine the mechanism. _x000D_ Methods: This is a multi-centre RCT set in the 5 cardiothoracic transplant units in the UK. We aim to recruit 152 adult patients on the list for lung transplantation. Patients that consent to recruitment will be allocated 1:1 to receive a SSF transplant alongside their lung transplant or standard lung transplant care with no SSF transplant. All other tests or treatments are at the discretion of the treating clinician. Participants will be followed-up at 6 weeks, 3, 6 and 12 months and in line with routine local clinical practice. The primary outcome is skin or organ rejection within 12 months, defined by biopsy-proven acute rejection . Secondary outcomes include clinical, safety and health-related quality of life outcomes. The diagnostic accuracy of the SSF will be assessed against the current reference standard. Mechanistic studies will identify the mechanism of immune-modulation by simultaneous transplant of skin/SOT and immune pathways in skin and SOT rejection. Long-term outcomes will be assessed at 5-years (beyond the duration of the grant) using routinely collected clinical and safety data from NHSBT._x000D_ Timelines for delivery: The total length of the grant is 60 months. Recruitment will last for 36 months. There will be a formal stop/go review of the internal pilot in month 18 of the project (after 9 months of recruitment) to ensure a minimum of 20 patients have been randomised and all centres have been opened to recruitment. If the target is met, the trial will continue to recruit for a further 27 months. _x000D_ Anticipated impact and Dissemination: If this trial shows the addition of a SSF is beneficial it is anticipated that SSFs will be adopted into NICE guidelines and become standard of care worldwide. Study results will be disseminated to participants via the SITU website, transplant units, NHSBT, patient groups and charities.

Research activity codes: 5.4 SURGERY;6.4 SURGERY
Health categories: RESPIRATORY;GENERIC HEALTH RELEVANCE