@article{0dd5c3ceec76476aaace3a910eadf606,
title = "Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial",
abstract = "Background: 3% of kidney transplant recipients return to dialysis annually upon allograft failure. Development of antibodies (Ab) against human leukocyte antigens (HLA) is a validated prognostic biomarker of allograft failure. We tested whether screening for HLA Ab, combined with an intervention to improve adherence and optimization of immunosuppression could prevent allograft failure. Methods: Prospective, open-labelled randomised biomarker-based strategy (hybrid) trial in 13 UK transplant centres [EudraCT (2012-004308-36) and ISRCTN (46157828)]. Patients were randomly allocated (1:1) to unblinded or double-blinded arms and screened every 8 months. Unblinded HLA Ab+ patients were interviewed to encourage medication adherence and had tailored optimisation of Tacrolimus, Mycophenolate mofetil and Prednisolone. The primary outcome was time to graft failure in an intention to treat analysis. The trial had 80% power to detect a hazard ratio of 0.49 in donor specific antibody (DSA)+ patients. Findings: From 11/9/13 to 27/10/16, 5519 were screened for eligibility and 2037 randomised (1028 to unblinded care and 1009 to double blinded care). We identified 198 with DSA and 818 with non-DSA. Development of DSA, but not non-DSA was predictive of graft failure. HRs for graft failure in unblinded DSA+ and non-DSA+ groups were 1.54 (95% CI: 0.72 to 3.30) and 0.97 (0.54–1.74) respectively, providing no evidence of an intervention effect. Non-inferiority for the overall unblinded versus blinded comparison was not demonstrated as the upper confidence limit of the HR for graft failure exceeded 1.4 (1.02, 95% CI: 0.72 to 1.44). The only secondary endpoint reduced in the unblinded arm was biopsy-proven rejection. Interpretation: Intervention to improve adherence and optimize immunosuppression does not delay failure of renal transplants after development of DSA. Whilst DSA predicts increased risk of allograft failure, novel interventions are needed before screening can be used to direct therapy. Funding: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).",
author = "Dominic Stringer and Leanne Gardner and Olivia Shaw and Brendan Clarke and David Briggs and Judith Worthington and Matthew Buckland and Guilherme Danzi and Rachel Hilton and Michael Picton and Thuraisingham, {Raj C} and Richard Borrows and Baker, {Richard J.} and Keith McCullough and John Stoves and Phanish, {Mysore K.} and Shiu, {Kin Yee} and Walsh, {Stephen B} and Aimun Ahmed and Waqar Ayub and Janet Hegarty and Rose Tinch-Taylor and Evangelos Georgiou and Natalie Bidad and Aysenur Kilic and Zoe Moon and Robert Horne and Paul McCrone and Joanna Kelly and Caroline Murphy and Janet Peacock and Anthony Dorling",
note = "Funding Information: Investigator-led, open label marker-based strategy (hybrid) randomised trial 16 , 17 conducted in 13 UK transplant units ( Suppl Fig. S1 ). Study conduct and patient safety were monitored by independent data monitoring and trial steering committees. Clinical coordination by the chief investigator (CI) was supported by the UK NIHR Clinical Research Networks. The study was approved by the MHRA and by the National Research Ethics Service Committee London (Hampstead) (12/LO/1759) and was carried out in accordance with the declaration of Helsinki (1996) and Good Clinical Practice as defined in UK clinical trial regulations. All subjects gave written informed consent. The trial is registered with EudraCT (2012-004308-36) and ISRCTN (46157828). Funding Information: Funding source and their role: The study was indemnified for negligent and non-negligent harm by King{\textquoteright}s College London. The study was funded by a National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme grant (ref 11/100/34 ). VH Bio (Gateshead, UK) provided reagents at cost price. This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. This study was supported by the United Kingdom Clinical Research Collaboration -registered King's Clinical Trials Unit at King's Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR Evaluation, Trials and Studies Coordinating Centre . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funders played no role in the writing of the manuscript nor in the decision to publish. Funding Information: The National Institute for Health Research Efficacy and Mechanism Evaluation programme grant (ref 11/100/34).AD declares research funding from the Medical Research Council, consulting fees (paid to KCL) from Hansa Biopharma, Verici Diagnostics, UCB Pharma and Quell Therapeutics, Membership of the Herperis Faculty 2019, 2021 and 2022 (expenses reimbursed), Membership of the UK Organ donation and transplantation research network executive since 2020 (unpaid), Membership of the EME funding Committee (2014–2019) and the EME funding committee subgroup (2018–2019) (both unpaid).Funding source and their role: The study was indemnified for negligent and non-negligent harm by King's College London. The study was funded by a National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme grant (ref 11/100/34). VH Bio (Gateshead, UK) provided reagents at cost price. This research was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. This study was supported by the United Kingdom Clinical Research Collaboration-registered King's Clinical Trials Unit at King's Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King's College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Funders played no role in the writing of the manuscript nor in the decision to publish. Publisher Copyright: {\textcopyright} 2023 The Authors",
year = "2023",
month = feb,
doi = "10.1016/j.eclinm.2022.101819",
language = "English",
volume = "56",
journal = "EClinicalMedicine",
issn = "2589-5370",
publisher = "Lancet Publishing Group",
}
