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. 2019 Aug 5;20(1):476.
doi: 10.1186/s13063-019-3602-2.

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

Dominic Stringer  1 , Leanne M Gardner  2 , Janet L Peacock  3 , Irene Rebollo-Mesa  4 , Rachel Hilton  5 , Olivia Shaw  6 , Richard Baker  7 , Brendan Clark  8 , Raj C Thuraisingham  9 , Matthew Buckland  10 , Michael Picton  11 , Judith Worthington  12 , Richard Borrows  13 , David Briggs  14 , Sapna Shah  15 , Kin Yee Shiu  16 , Keith McCullough  17 , Mysore Phanish  18 , Janet Hegarty  19 , John Stoves  20 , Aimun Ahmed  21 , Waqar Ayub  22 , Robert Horne  23 , Paul McCrone  24 , Joanna Kelly  25 , Caroline Murphy  25 , Anthony Dorling  2
Affiliations

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

Dominic Stringer et al. Trials. .

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.

Keywords: Graft failure; Human leucocyte antigen antibodies; Immunosuppression; Randomised controlled trial; Renal transplantation; Statistical analysis plan; Time-to-event.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
OuTSMART flow diagram. *Randomisation performed on results of a recruit’s first screening test. Those with human leucocyte antigen (HLA) antibodies (Ab) undergo no further screening as part of the trial (but serum will be stored for analysis of HLA Ab profiles later). †Those initially HLA Ab− undergo routine screening every 8 months. There is no second randomisation: if a recruit allocated to blinded standard care (group C) becomes HLA Ab+ (black lines), they remain in the standard care group (group A1 or A2). If in unblinded standard care group (D), they change to unblinded biomarker-led treatment care (group B1 or B2) (orange lines). €Numbers in each group are those anticipated at the end of study
Fig. 2
Fig. 2
Consolidated Standards of Reporting Trials (CONSORT) diagram for OuTSMART. Ab antibody, HLA human leucocyte antigen, DSA donor-specific antibodies
See this image and copyright information in PMC

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References

    1. Dorling A, Rebollo-Mesa I, Hilton R, Peacock JL, Vaughan R, Gardner L, et al. Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial. Trials. 2014;15(1):30. doi: 10.1186/1745-6215-15-30. - DOI - PMC - PubMed
    1. George B, Seals S, Aban I. Survival analysis and regression models. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol. 2014;21(4):686–694. doi: 10.1007/s12350-014-9908-2. - DOI - PMC - PubMed
    1. Cytel Inc., Cambridge MA. East 6 (2016). Statistical software for the design, simulation and monitoring clinical trials. https://www.cytel.com/software-solutions/east/faq.
    1. Lachmann N, Terasaki PI, Budde K, Liefeldt L, Kahl A, Reinke P, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation. 2009;87(10):1505–1513. doi: 10.1097/TP.0b013e3181a44206. - DOI - PubMed
    1. Dudley C, Pohanka E, Riad H, Dedochova J, Wijngaard P, Sutter C, et al. Mycophenolate mofetil substitution for cyclosporine A in renal transplant recipients with chronic progressive allograft dysfunction: The ‘Creeping Creatinine’ Study. Transplantation. 2005;79(4):466–475. doi: 10.1097/01.TP.0000151632.21551.00. - DOI - PubMed

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