Update to the study protocol, including statistical analysis plan, for the multicentre, randomised controlled OuTSMART trial: a combined screening/treatment programme to prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies

Abstract

Background Chronic rejection is the single biggest cause of premature kidney graft failure. HLA antibodies (Ab) are an established prognostic biomarker for premature graft failure so there is a need to test whether treatment decisions based on the presence of the biomarker can alter prognosis. The Optimised TacrolimuS and MMF for HLA Antibodies after Renal Transplantation (OuTSMART) trial combines two elements. Firstly, testing whether a routine screening programme for HLA Ab in all kidney transplant recipients is useful by comparing blinding versus unblinding of HLA Ab status. Secondly, for those found to be HLA Ab+, testing whether the introduction of a standard optimisation treatment protocol can reduce graft failure rates. Methods OuTSMART is a prospective, open-labelled, randomised biomarker-based strategy (hybrid) trial, with two arms stratified by biomarker (HLA Ab) status. The primary outcome was amended from graft failure rates at 3 years to time to graft failure to increase power and require fewer participants to be recruited. Length of follow-up subsequently is variable, with all participants followed up for at least 43 months up to a maximum of 89 months. The primary outcome will be analysed using Cox regression adjusting for stratification factors. Analyses will be according to the intention-to-treat using all participants as randomised. Outcomes will be analysed comparing standard care versus biomarker-led care groups within the HLA Ab+ participants (including those who become HLA Ab+ through re-screening) as well as between HLA-Ab-unblinded and HLA-Ab-blinded groups using all participants. Discussion Changes to the primary outcome permit recruitment of fewer participants to achieve the same statistical power. Pre-stating the statistical analysis plan guards against changes to the analysis methods at the point of analysis that might otherwise introduce bias through knowledge of the data. Any deviations from the analysis plan will be justified in the final report. Trial registration ISRCTN registry, ID: ISRCTN46157828 . Registered on 26 March 2013; EudraCT 2012–004308-36 . Registered on 10 December 2012.

On the clinical relevance of using complete high-resolution HLA typing for an accurate interpretation of posttransplant immune-mediated graft outcomes

“…However, while complete HR HLA typing has shown its clinical value in the pretransplant setting, the impact of this biological information in the management of patients after transplantation has not been assessed yet. Notably, while there is still no clear evidence on how to manage transplant patients developing dnDSA, allograft biopsies to rule out ongoing immune-mediated lesions and enhancement of the immunosuppression burden are frequently performed ( 10 – 12 ). Therefore, the precise identification that such de novo anti-HLA antibodies are indeed directed against donor (HLA)-specific antigens is highly warranted to avoid invasive procedures and unnecessary rescue immunosuppressive therapies and, furthermore, to recognize those patients with true dnDSA to establish guided therapeutic strategies.…”

Optimized immunosuppression to prevent graft failure in renal transplant recipients with HLA antibodies (OuTSMART): a randomised controlled trial

“…In HLA Ab-negative groups, at least 672 patients would allow observation of 22/337 (6.5%) graft losses in SC, and 32/335 (9.5%) in BLC, providing 90% power to demonstrate non-inferiority with an assumed HR of 1.4 under the null hypothesis, and a HR of 0.63 under the alternative one-sided 95% Confidence Interval of the HR estimated using a Cox regression model. Further details have been published previously 16 and are in the Supplementary File.…”

“…Investigator-led, open label marker-based strategy (hybrid) randomised trial 16,17 conducted in 13 UK transplant units (Suppl Fig. S1).…”

“…In OuTSMART, we tested the hypothesis that routine surveillance for the development of HLA Ab, combined with an intervention to improve adherence, followed by tailored optimised oral treatment in those who became HLA Ab+, would prevent the kidney allograft failure. 15,16…”

“…The primary endpoint was to be evaluated remotely at a minimum of 43 months post-randomisation. 16 However, in 2020, as the influence of the 'first wave' of the COVID-19 pandemic on UK transplant recipient death rates became obvious, clinical research teams were re-deployed and routine patient visits to all hospitals were cancelled, we had to re-define the primary endpoint as that obtained at the last follow-up prior to 16th March 2020. Other changes to the protocol are described in detail in the Supplementary Appendix.…”